All-natural enteric soft capsules

ABSTRACT

Described herein are soft capsules and enteric soft capsules comprising cationic Type A gelatin and acid insoluble enteric polymers. In particular, the compositions and methods for manufacturing all-natural enteric soft capsules comprising Type A gelatin and matrix fills are described. In one embodiment, the enteric soft capsules comprise active ingredients such as non-steroidal anti-inflammatory drugs (NSAIDs). In another embodiment, the enteric soft capsule comprises matrix fills of omega-3 fatty acids.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/404,368, filed Jan. 12, 2017, which is a divisional application ofU.S. patent application Ser. No. 14/745,485, filed Jun. 22, 2015, whichclaims priority to U.S. Provisional Patent Application Nos. 62/015,818,and 62/015,821, both filed Jun. 23, 2014, and 62/065,791, filed Oct. 20,2014, each of which are incorporated by reference herein in itsentirety.

TECHNICAL FIELD

Described herein are soft capsules and enteric soft capsules comprisingcationic Type A gelatin and acid insoluble enteric polymers. Inparticular, the compositions and methods for manufacturing all-naturalenteric soft capsules comprising Type A gelatin and matrix fills aredescribed. In some embodiments, the enteric soft capsules compriseactive ingredients such as non-steroidal anti-inflammatory drugs(NSAIDs) or omega-3 fatty acids.

BACKGROUND

The use and manufacture of oral enteric dosage forms are known in theart. Such dosage forms have been explained and reviewed in referenceworks, e.g., in Remington's Pharmaceutical Sciences, 18^(th) edition,Mack Publishing Co., Easton, Pa. (1990). Enteric dosage forms aredesirable, either to protect the content of the dosage form from thegastric conditions or to protect the gastric tissue from an irritantmaterial contained in the enteric dosage form. The protection of gastricand esophageal tissues using enteric dosage forms is very important forthe sustained use of non-steroidal anti-inflammatory drugs in conditionssuch as chronic pain, osteoarthritis, and rheumatoid arthritis.

A further use for enteric dosages is for the prevention of a lasting,unacceptable mouth odor resulting from ingestion of substances likegarlic or fish oil. Furthermore, in some cases all-natural fish oilcapsules containing omega-3 fatty acids are desirable to consumers.

Enteric dosage forms are also used to provide slow, controlled, ordelayed release of a substance.

To fulfill the compendium definition requirement for enteric orgastro-resistant preparations, these preparations have to pass specificcompendia tests. The enteric or gastro-resistant property is obtainedonly if the enteric dosage form does not dissolve or disintegrate ingastric acidity for a specified amount of time (usually two hours in 0.1N hydrochloric acid, pH ca. 1.2 at 37° C.). Further, the enteric dosageforms must release their contents in simulated intestinal environments(e.g., in buffers of pH values at about 6.8) within certain timeperiods. Detailed evaluation techniques are described in national andinternational pharmacopoeia.

The majority, if not all, of the enteric dosage forms currently in useare produced by a film-coating process, where a thin film layer ofacid-insoluble (enteric) polymer is accumulated on the surface of apre-manufactured dosage form. Dosage forms coated in this manner havebeen mainly tablets and, to a lesser extent, hard or soft capsules. Theenteric coating method involves spraying of an aqueous or organicsolution or a suspension of enteric polymers onto tumbling or movingtablets or capsules, accompanied by drying using hot air.

Enteric dosage forms made by coating suffer from various process-relatedproblems and defects that affect their performance or appearance. Forexample, “orange peel” surface formation, also known as surfaceroughness, mottling, or lack of surface homogeneity may result. Inaddition, coat integrity failure may occur, such as in cases of crackingor flaking of the coating. All coatings present inherent problems,including possible uneven distribution of the coating ingredients, whichcan easily happen under the multivariate coating process. These failuresof enteric coatings reduce the effectiveness of said coating inpreventing painful and often harmful gastric and esophagealdisturbances.

The foregoing problems of enteric coatings are shared by all entericdosage forms such as tablets and capsules. However, the problems facedduring coating of capsules are even more critical, due to the delicateand heat sensitive nature of the soft elastic capsule shell. Both hardand soft capsules can easily undergo agglomeration and distortion due tothe heat-sensitive shell composition. Moreover, the smoothness andelasticity of the capsule surface make it difficult to form an intactadhering enteric coat without careful sub-coating steps to improve thesurface for coating. A further disadvantage of enteric coating for softcapsules is the loss of the normally shiny and clear appearance ofcapsule gelatin shells. The elegant, clear gelatin shell has been asignificant reason for soft capsule popularity and acceptance. Inaddition to the undesirable surface texture modifications usually causedby coating, most accepted aqueous enteric polymer preparations result inopaque capsules.

Medical professionals are increasingly recognizing the positivecardiovascular health benefits of fish oil based products. The principleoral dosage of fish oil is through soft gelatin capsules. However, amajor limitation for consumers and patient compliance for the continuedtaking of these fish oil products is the presence of disruptive andunpleasant fishy odors associated with these traditional soft gelatinfish oil capsules. In particular, taking fish oil can result in negativeside effects, including but not limited to, gastric disturbances such asfishy eructation (belching, e.g., “fishy burps”), gastrointestinaldiscomfort, bloating, nausea, diarrhea, unpleasant fishy odor, orunpleasant fishy aftertaste.

To minimize these negative side effects, consumers often will freezetheir fish oil capsules before ingestion, which is thought topotentially prevent break down of the capsule in the esophagus andstomach. Several commercial products offer enterically coated fish oilsoft gelatin capsules to help circumvent capsule break down in thestomach. Other products include flavors or odor masking agents such ascitrus or vanilla. However, these agents do not solve the negative sideeffects. In addition, there are significant problems associated withtraditional enteric coated capsules.

In addition, consumers have expressed a desire for nutraceuticals ordietary supplements made of all-natural ingredients. Thus, compositionspromoting “All-Natural Ingredients” are appealing to nutrition-consciousconsumers compared to products containing artificial ingredients.

Accordingly, it is desirable to develop an oral delivery system thatprovides enteric properties and that utilize all-natural ingredients,especially for use with fish oil or non-steroidal anti-inflammatorydrugs.

Therefore, the enteric oral soft capsules described herein, have robustacid-resistant capsule shells, and are not enterically coated. Moreover,the soft capsules described herein, are easy to ingest.

SUMMARY

Described herein are compositions and methods for manufacturing forall-natural oral enteric soft capsules.

One embodiment described herein is an all-natural enteric soft capsuleshell composition comprising: (a) a gelatin composition; (b) an anionicpolysaccharide; (c) a plasticizer; and (d) a solvent. In one aspectdescribed herein: (a) the gelatin composition comprises Type A gelatinhaving a Bloom strength of 175 grams; (b) the anionic polysaccharidecomprises pectin; (c) the plasticizer comprises glycerol; and (d) thesolvent comprises water. In one aspect described herein: (a) the gelatincomposition comprises pig skin Type A gelatin comprising 33.2% of thetotal composition or acid bone Type A gelatin comprising 36% of thetotal composition; (b) the anionic polysaccharide comprises pectincomprising about 3.3% of the total composition; (c) the plasticizercomprises glycerol comprising about 16% of the total composition; and(d) the solvent comprises water comprising about 47% or about 44% of thetotal composition. In one aspect described herein: (a) the gelatincomposition comprises about 33.2% pig skin Type A gelatin; (b) theanionic polysaccharide comprises about 3.3% pectin; (c) the plasticizercomprises about 16% glycerol; and (d) the solvent comprises about 47%water.

Another embodiment described herein is an enteric soft capsulecomprising a shell comprising the compositions as described herein. Inone aspect described herein, the enteric soft capsule comprises a matrixfill that is liquid, semi-solid, or solid. In one aspect describedherein, the enteric soft capsule shell does not dissolve in simulatedgastric fluid (pH 1.2) for at least 2 hours, and begins dissolution insimulated intestinal fluid (pH 6.8) within about 10 minutes. In oneaspect described herein, the enteric soft capsule shell is clear ortransparent. In one aspect described herein, the enteric soft capsuleshell is transparent and colored. Another embodiment described herein isa method for preparing an all-natural enteric soft capsule shellcomprising: (a) combining dry shell components comprising a gelatincomposition and an anionic polymer together to form a dry mixture; (b)adding plasticizer and solvent to the dry mixture with agitation to forma wet mixture; (c) heating the wet mixture with agitation and applyingvacuum deaeration to form a gel mass; (d) heating the gel mass for anadditional period; (e) forming an enteric soft capsule using rotary dietechnology; and (f) drying the enteric soft capsules. In one aspectdescribed herein, the wet mixture is heated to about 30° C. to about 90°C. prior to vacuum deaeration. In one aspect described herein, the wetmixture is heated to about 75° C. to about 90° C. prior to vacuumdeaeration. In one aspect described herein, the temperature ismaintained for a period of about 15 minutes to about 60 minutes. In oneaspect described herein, the vacuum deaeration is applied for betweenabout 1 hours to about 6 hours to form a gel mass. In one aspectdescribed herein, the gel mass is heated to about 75° C. to about 90° C.for between about 0.5 hours to about 72 hours.

Another embodiment described herein is an all-natural enteric softcapsule formed according to the method described herein, wherein thefinal moisture content of the all-natural enteric soft capsule shellafter the drying step is from about 5% to about 16%. In one aspectdescribed herein the capsule further comprises an active ingredient inthe matrix fill. In one aspect described herein, the all-natural entericsoft capsule shell is stable at pH 1.2 for at least 2 hours. In oneaspect described herein, the all-natural enteric soft capsule shelldissolves at pH 6.8 within 30 minutes. In one aspect described herein,the all-natural enteric soft capsule comprises a matrix fill that isliquid, semi-solid, or solid. In one aspect described herein, theall-natural enteric soft capsule shell is clear or transparent. In oneaspect described herein, the all-natural enteric soft capsule shell istransparent and colored. In one aspect described herein, the thicknessof the all-natural enteric soft capsule shell is from about 0.010 inchesto about 0.050 inches.

Another embodiment described herein is a pharmaceutical compositioncomprising an all-natural enteric soft capsule as described herein.

Another embodiment described herein is a method for treating,ameliorating the symptoms of, or delaying the onset of a medicalcondition by providing a subject in need thereof with the pharmaceuticalcomposition described herein, further comprising an activepharmaceutical ingredient or a nutraceutical.

Another embodiment described herein is a soft capsule pharmaceuticalcomposition comprising a matrix fill comprising: (a) at least onesolubility enhancing agent; (b) at least one plasticizer; (c) water; and(d) at least one active pharmaceutical ingredient. In one aspectdescribed herein, the one or more solubility enhancing agents comprisesabout 10% to about 85% of the matrix fill mass. In one aspect describedherein, the one or more solubilizing plasticizers comprises about 2.5%to about 10% of the matrix fill mass. In one aspect described herein,water comprises about 2.5% to about 20% of the matrix fill mass. In oneaspect described herein, the one or more active pharmaceuticalingredients comprises about 5% to about 80% of the matrix fill mass. Inone aspect described herein: (a) the one or more solubility enhancingagents comprises polyethylene glycol having a molecular weight of about200 to about 800; (b) the one or more solubilizing plasticizerscomprises glycerol or propylene glycol; (c) the one or more activepharmaceutical ingredients comprises a non-steroidal anti-inflammatorydrug. In one aspect described herein: (a) the one or more solubilityenhancing agent comprises polyethylene glycol have a molecular weight ofabout 600 comprising about 80% of the matrix fill mass; (b) the one ormore solubilizing plasticizer comprises glycerol comprising about 5% ofthe matrix fill mass or propylene glycol comprising about 5% of thematrix fill mass; (c) water comprises about 5% of the matrix fill mass;and (d) the one or more active pharmaceutical ingredient comprisesdiclofenac potassium comprising about 11% of the matrix fill mass.

Another embodiment described herein is a method for preparing matrixfills as described herein comprising sequentially combining the matrixfill components comprising polyethylene glycol having a molecular weightof about 600, propylene glycol, water, and diclofenac potassium andheating the wet mixture under agitation until a clear or transparentsolution is observed.

Another embodiment described herein is a soft capsule pharmaceuticalcomposition comprising a matrix fill comprising: (a) at least onewetting agent; (b) at least one lipophilic liquid; (c) at least onesemi-solid lipophilic substance; (d) at least one hydrophilicpolysaccharide; (e) at least one hydrophilic polymer; and (f) at leastone active pharmaceutical ingredient. In one aspect described herein,the one or more wetting agents comprises about 1% to about 3% of thematrix fill mass. In one aspect described herein, the one or morelipophilic liquids comprises about 20% to about 70% of the matrix fillmass. In one aspect described herein, the one or more semi-solid liquidsubstances comprises about 2% to about 7% of the matrix fill mass. Inone aspect described herein, the one or more hydrophilic polysaccharidescomprises about 2% to about 10% of the matrix fill mass. In one aspectdescribed herein, the one or more hydrophilic polymers comprises about2% to about 10% of the matrix fill mass. In one aspect described herein,the active pharmaceutical ingredient comprises about 60% of the matrixfill mass.

Another embodiment described herein, (a) the one or more wetting agentscomprises lecithin; (b) the one or more lipophilic liquids comprisesvegetable oil and soybean oil; (c) the one or more semi-solid lipophilicsubstances comprises bee's wax; (d) the one or more hydrophilicpolysaccharides comprises chitosan; (e) the one or more hydrophilicpolymers comprises Carbopol® 971; and (f) the one or more activepharmaceutical ingredients comprises a non-steroidal anti-inflammatorydrug. In one aspect described herein, (a) the wetting agent compriseslecithin comprising about 1.5% of the matrix fill mass; (b) thelipophilic liquid comprises vegetable oil comprising about 12.5% of thematrix fill mass and soybean oil comprising about 53% of the matrix fillmass; (c) the semi-solid lipophilic substance comprises bee's waxcomprising about 3% of the matrix fill mass; (d) the hydrophilicpolysaccharide comprises chitosan comprising about 5% of the matrix fillmass; (e) the hydrophilic polymer comprises Carbopol® 971 comprisingabout 5% of the matrix fill mass; and (f) the active pharmaceuticalingredient comprises diclofenac potassium comprising about 20% of thematrix fill mass.

Another embodiment described herein is a method for preparing matrixfills as described herein comprising: (a) combining the specifiedamounts of wetting agent, lipophilic liquids, semi-solid lipophilicsubstance to form a first mixture; (b) heating said first mixture to 65°C. under agitation; (c) adding the specified amounts of hydrophilicpolymer, hydrophilic polysaccharide, and active pharmaceuticalingredient to the said heated first mixture to form a second mixture;and (d) mixing and de-airing said second mixture to form a matrix fill.In one aspect described herein, the non-steroidal anti-inflammatory drugcomprises diclofenac in its salt or free acid form comprising diclofenacpotassium, diclofenac sodium, diclofenac hydrochloride, or diclofenacfree acid. In one aspect described herein, diclofenac comprises a weightof about 25 mg to about 150 mg. In one aspect described herein, whereinthe matrix fill mass is about 80 mg to about 500 mg.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising an enteric soft capsule shell comprising: (a) agelatin composition comprising a Type A gelatin; (b) at least oneacid-insoluble polymer or anionic polysaccharide comprising amethacrylic acid copolymer (e.g., EUDRAGIT® L 100) or pectin; (c) atleast one plasticizer comprising glycerol; (d) optionally at least onealkali neutralizing agent comprising ammonia; and (e) water; wherein,the oral pharmaceutical composition further comprises a matrix fillcomprising: (a) at least one solubility enhancing agent comprisingpolyethylene glycol 600; (b) at least one plasticizer comprisingglycerol; (c) water; and (d) at least one active pharmaceuticalingredient comprising a non-steroidal anti-inflammatory drug; or (e) oneor more wetting agents comprising lecithin; (f) one or more lipophilicliquids comprising vegetable oil and soybean oil; (g) one or moresemi-solid lipophilic substances comprising bee's wax; (h) one or morehydrophilic polysaccharides comprising chitosan; (i) one or morehydrophilic polymers comprising Carbopol® 971; and (j) one or moreactive pharmaceutical ingredients comprising a non-steroidalanti-inflammatory drug.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising an enteric soft capsule shell comprising: (a) pigskin Type A gelatin comprising about 33.2% of the shell mass or acidbone Type A gelatin comprising about 36% of the shell mass; (b) pectincomprising about 3.3% of the total gel mass or EUDRAGIT® L 100comprising about 11% of the shell mass; (c) a plasticizer comprisingglycerol comprising about 16% or about 18% of the shell mass; (d) anoptional alkali neutralizing agent comprising about 1.7% of the shellmass; and (e) a solvent comprising about 47% or about 44% of the shellmass; and wherein, the oral pharmaceutical composition further comprisesa matrix fill comprising: (a) polyethylene glycol 600 comprising about80% of the matrix fill mass; (b) propylene glycol comprising about 5% ofthe matrix fill mass; (c) water comprising about 5% of the matrix fillmass; and (d) diclofenac potassium comprising about 11% of the matrixfill mass; or (e) lecithin comprising about 1.5% of the matrix fillmass; (f) vegetable oil comprising about 12.5% of the matrix fill massand soybean oil comprising about 53% of the matrix fill mass; (g) bee'swax comprising about 3% of the matrix fill mass; (h) chitosan comprisingabout 5% of the matrix fill mass; (i) Carbopol® 971 comprising about 5%of the matrix fill mass; and (j) diclofenac potassium comprising about20% of the matrix fill mass.

Another embodiment described herein is an all-natural oral entericpharmaceutical composition comprising a soft enteric capsule shell and amatrix, the capsule shell comprising: (a) a gelatin composition; (b) atleast one or more anionic polymer; (c) at least one or more plasticizer;and (d) water; and the matrix fill comprising: (e) one or more fattyacids, one or more fat-soluble vitamins, or a combination thereof. Inone aspect described herein, the fatty acid comprises omega-3 fattyacids, polyunsaturated omega-3 fatty acids, hexadecatrienoic acid (HTA),alpha-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid(ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA,timnodonic acid), heneicosapentaenoic acid (HPA), docosapentaenoic acid(DPA), clupanodonic acid), docosahexaenoic acid (DHA, cervonic acid),tetracosapentaenoic acid, tetracosahexaenoic acid (nisinic acid),arachidonic acid and free acids, etheyl esters, or other esters or saltsand combinations thereof. In one aspect described herein, theall-natural enteric soft capsule size is defined as being from about 2oval to about 8 oval or about 2 round to about 8 round. In one aspectdescribed herein, the composition is useful for treating, retarding theprogression of, delaying the onset of, prophylaxis of, amelioration of,or reducing the symptoms a medical condition.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a medical condition by administering toa subject in need thereof the pharmaceutical composition describedherein.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of mild, moderate, or severe pain stemmingfrom arthritis, tendonitis, bursitis, dysmenorrhea, endometriosis,chronic neuropathies, shingles, sports injuries, cancer, ormalignancies; inflammation; mild, moderate, or severe fever; migraines;osteoarthritis; rheumatoid arthritis; ankylosing spondylitis;spondylarthritis; gout; pain associated with kidney stones; or acombination thereof, the method comprising administering to a subject inneed thereof the oral pharmaceutical composition according to claims63-64, without substantially inducing one or more of esophagealirritation, esophageal erosion, gastric irritation, gastric reflux, orpeptic ulcers.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a cardiovascular-related diseaseincluding, but not limited to, hyperlipidemia or hypertriglyceridemia,the method comprising administering to a subject in need thereof theoral pharmaceutical composition as described herein, withoutsubstantially inducing one or more of one or more of eructation,abdominal discomfort, nausea, diarrhea, or unpleasant fishy odor.

Another embodiment described herein is a kit for dispensing the oralpharmaceutical composition as described herein, comprising: (a) at leastone enteric soft capsule comprising a matrix fill that further comprisesat least about 25 mg to about 500 mg of an active pharmaceuticalingredient; (b) at least one receptacle comprising a tamper evident,moisture proof packaging that reduces the ability of removing the oralpharmaceutical composition comprising blister or strip packs, aluminumblister, transparent or opaque polymer blister with pouch, polypropylenetubes, colored blister materials, tubes, bottles, and bottles optionallycontaining a child-resistant feature, optionally comprising a desiccant,such as a molecular sieve or silica gel; (c) optionally, an insertcomprising instructions or prescribing information for the activepharmaceutical ingredient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Delayed release of enteric soft capsules comprising thecomposition of Table 16.

FIG. 2. Ribbon strength versus gel viscosity of the enteric softcapsules comprising the compositions of Table 10.

FIG. 3. Dissolution of enteric soft capsules in pH 6.8 phosphate buffercomprising diclofenac (average of six experiments).

DETAILED DESCRIPTION

Described herein are compositions and methods for manufacturing softcapsules containing gelatin that are in some aspects made of all-naturalingredients.

As used herein, the term “all-natural” refers to the enteric softcapsule shell and means that the enteric soft capsule shell does notcomprise any synthetic or artificial components.

As used herein, the phrase “pharmaceutical composition” encompasses“nutritional compositions” or “nutritional supplements.”

As used herein, the terms “gastric-resistant” and “enteric” are usedinterchangeably and refer to the property of a substance resistantdissolution in biological, artificial, or simulated gastric fluid (pHca. 1.2), and that dissolves in biological, artificial, or simulatedintestinal fluid (pH ca. 6.8). One embodiment described herein isgastric-resistant or enteric soft capsules.

As used herein, the term “fatty acid” refers to any carboxylic acidhaving a long aliphatic chain that can be either saturated orunsaturated. The term fatty acid further encompasses any fish oildescribed herein and any saturated, polyunsaturated, monounsaturated, orany omega-3, -6, -7, or -9 fatty acid.

As used herein, the term “bioavailability” refers to the proportion ofan active pharmaceutical ingredient that enters the systemic circulationwhen introduced into the body and is able to have a physiologicaleffect.

As used herein, the term “enhanced bioavailability” refers to theincreased proportion of an active pharmaceutical ingredient that entersthe systemic circulation when introduced into the body as compared to areference's bioavailability.

As used herein, the term “absolute bioavailability” refers to thefraction of a drug or active pharmaceutical ingredient absorbed throughnon-intravenous administration (e.g., oral administration) as comparedto intravenous administration of the same drug or active pharmaceuticalingredient.

As used herein, the term “polyunsaturated fatty acid” (“PUFA”) refers toa long chain fatty acid that contains more than one double bond in thebackbone of the chain. The term encompasses esters, re-esterifiedtriglycerides, or salts thereof.

As used herein, the term “monounsaturated fatty acid” refers to a longchain fatty acid that contains only one double bond in the backbone ofthe chain. The term encompasses esters, re-esterified triglycerides, orsalts thereof.

As used herein, the terms “active ingredient,” “active pharmaceuticalingredient,” or “active pharmaceutical agent” refer to an agent, activeingredient, compound, or substance, compositions, or mixtures thereof,that provide a pharmacological, often beneficial, effect. Reference to aspecific active ingredient includes, where appropriate, the activeingredient and any of its pharmaceutically acceptable free acids, freebases, salts, or esters.

As used herein, the terms “dosage” or “dose” denote any form of theactive ingredient formulation that contains an amount sufficient toproduce a therapeutic effect with a single administration. The dosageform used herein is for oral administration. The preferred oral dosageforms are soft capsules or enteric soft capsules.

As used herein, the phrase “enteric soft capsule composition,” “entericsoft capsule,” “enteric soft capsule gel mass,” “gel mass,” or “entericsoft capsule shell” are used interchangeably and have the same meaning.Typically, as used herein, “enteric soft capsule composition” or “gelmass” refer to enteric soft capsule compositions prior to forming theenteric soft capsule and “enteric soft capsule shell” refers to theenteric capsule shell after having been formed into an enteric softcapsule, for example, by using rotary die encapsulation. When thephrases “enteric soft capsule composition,” “enteric soft capsule,”“enteric soft capsule gel mass,” “gel mass,” or “enteric soft capsuleshell” are used herein without the preceding phrase “all-natural,” theshell may contain synthetic or artificial components.

As used herein, the terms “matrix,” “matrix composition,” “matrix fill,”“fill composition,” or “fill” all refer to a composition that isencapsulated by a capsule shell and may optionally contain an activepharmaceutical ingredient.

As used herein, the term “pharmaceutical composition” refers acomposition comprising at least on active ingredient, nutraceutical,nutritional, or vitamin. In some embodiments described herein, apharmaceutical composition comprises a soft capsule shell having beenformed into a capsule, for example, using rotary die encapsulationcomprising one or more polyunsaturated fatty acids, optionally with oneor more vitamins, antioxidants, or other active ingredients.

The term “formulation” or “composition” as used herein refers to theactive pharmaceutical ingredient, nutraceutical, nutritional, vitamin,or drug in combination with pharmaceutically acceptable excipients. Thisincludes orally administrable formulations as well as formulationsadministrable by other means.

The term “controlled release” as used herein refers to a compositionthat does not immediately release an active ingredient. “Controlledrelease” as used herein encompasses the terms “modified release,”“sustained release,” “extended release,” and “delayed release.”

The term “delayed release” as used herein refers to a composition thatreleases an active ingredient according to a desired profile over anextended period under physiological conditions or in an in vitro test.By “extended period” it is meant a continuous period of time of at leastabout 20 minutes, about 30 minutes, about 1 hour; about 2 hours; about 4hours; about 6 hours; about 8 hours; about 10 hours; about 12 hours;about 14 hours; about 16 hours; about 18 hours; about 20 hours; about 24hours; or even longer.

The term “modified release” as used herein refers to a composition thatreleases an active ingredient at a slower rate than does an immediaterelease formulation under physiological conditions or in an in vitrotest.

The term “sustained” release” as used herein refers to a compositionthat releases an active ingredient over an extended period of time, forexample minutes, hours, or days, such that less than all the activeingredient is released initially. A sustained release rate may provide,for example, a release of a certain specified amount of a drug or activeingredient from a dosage form, over a certain period, underphysiological conditions or in an in vitro test.

The term “extended release” as used herein refers to a composition thatreleases an active ingredient over an extended period, such as of atleast about 20 minutes, about 30 minutes, about 1 hour; about 2 hours;about 4 hours; about 6 hours; about 8 hours; about 10 hours; about 12hours; about 14 hours; about 16 hours; about 18 hours; about 20 hoursabout 24 hours; or even longer; specifically over a period of at least18 hours under physiological conditions or in an in vitro assay.

The term “C_(max)” as used herein refers to the maximum observed blood(plasma, serum, or whole blood) concentration or the maximum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(min)” as used herein refers to the minimum observed blood(plasma, serum, or whole blood) concentration or the minimum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(avg)” as used herein refers to the blood (plasma, serum, orwhole blood) concentration of the drug within the dosing interval, iscalculated as AUC/dosing interval, and is expressed in units of mg/L orng/mL, as applicable.

The term “T_(max)” as used herein refers to the time afteradministration at which C_(max) occurs, and is expressed in units ofhours (h) or minutes (min), as applicable.

The term “AUC_(0→τ)” as used herein refers to area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime zero to time tau (τ) over a dosing interval at steady state, wheretau is the length of the dosing interval, and is expressed in units ofh·mg/L or h·ng/mL, as applicable. For example, the term AUC_(0→12) asused herein refers to the area under the concentration versus time curvefrom 0 to 12 hours.

The term “AUC_(0→∞)” as used herein refers to the area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime 0 hours to infinity, and is expressed in units of h·mg/L orh·ng/mL, as applicable.

The term “room temperature” as used herein refers to common ambienttemperatures ranging from about 20° C. to about 27° C.

The term “treating” refers to administering a therapy in an amount,manner, or mode effective to improve a condition, symptom, or parameterassociated with a disorder.

The term “prophylaxis” refers to preventing or reducing the progressionof a disorder, either to a statistically significant degree or to adegree detectable to one skilled in the art.

The term “substantially” as used herein means to a great or significantextent, but not completely.

The term “about” as used herein refers to any values, including bothintegers and fractional components that are within a variation of up to±10% of the value modified by the term “about.” For example, the phrase“about 50%” is equivalent to any vale ≈50±10%, e.g., 44.6%, 45%, 46%,47%, 48%, 49%, 49.5%, 50%, 50.3%, 51%, 52%, 53%, 54%, 55%, inter alia.

As used herein, “a” or “an” means one or more unless otherwisespecified.

Terms such as “include,” “including,” “contain,” “containing,” “has,” or“having,” and the like, mean, “comprising.”

The term “or” can be conjunctive or disjunctive.

One embodiment described herein is an all-natural enteric soft capsulecomposition comprising a gelatin composition ionically bonded withanionic enteric polymers. The enteric soft capsule shell can compriseone or more types of gelatin, one or more anionic enteric polymers, oneor more plasticizers, one or more solvents, and optionally colorings,gelling agents, flavorings, or other conventionally acceptedpharmaceutical excipients or additives.

The all-natural enteric soft capsules described herein can be used fororal delivery of active pharmaceutical ingredients, nutraceuticals, ornutritionals that are irritating to the stomach, that are sensitive tothe acidity of the stomach, or that have unpleasant tastes or odors. Theenteric soft capsules described herein do not dissolve in the gastricenvironment (pH ca. 1.2), but readily dissolve in the intestinalenvironment (pH ca. 6.8).

Enteric soft capsules are described generally in International PatentApplication Publication Nos. WO 2004/030658 and WO 2007/075475 and U.S.Patent Application Publication Nos. US 2006/0165778 and US 2010/0158958,each of which is incorporated by reference herein for such teachings.The enteric soft capsule shell can comprise one or more film formingpolymers, one or more enteric acid insoluble polymers, one or moreplasticizers, one or more alkali neutralizing agents, one or moresolvents, optionally one or more colorants, and optionally one or moreflavorings and/or other conventionally accepted pharmaceuticalexcipients or additives.

Film-former polymers that are useful for creating enteric soft capsulesare gelatin or hydroxypropylmethylcellulose (HPMC). In one aspect of theenteric soft capsule shell described herein, the film-forming polymer isgelatin. Examples of gelatin compositions that are useful for creatingenteric soft capsules described herein comprise acid bone gelatin, limebone gelatin, pig skin gelatin, chicken skin gelatin, fish gelatin, acidhide gelatin, gelatin hydrolysate, or combinations thereof. The strengthof said gelatin compositions are often defined by their Bloom strengthor grade in the range of about 30 Bloom to about 400 Bloom.

Examples of enteric, anionic polysaccharides, as described herein,comprise polygalacturonic acid, carboxymethyl pullulan, carboxymethylcellulose, hyaluronic acid, cellulose phthalate, cellulose succinate,alginate, sodium alginate, and pectin, acrylic and methacrylate acidcopolymers, cellulose acetate phthalate (CAP), cellulose acetatebutyrate, hydroxypropylmethylcellulose phthalate (HPMCP), algenic acidsalts such as sodium or potassium alginate, or shellac. Poly(methacylicacid-co-methyl methacrylate) anionic copolymers based on methacrylicacid and methyl methacrylate are particularly stable and are preferredin some embodiments. Poly(meth)acrylates (methacrylic acid copolymer),available under the trade name EUDRAGIT® (Evonik Industries AG, Essen,Germany), are provided as powder or aqueous dispersions. In one aspect,the methacrylic acid copolymer can be EUDRAGIT® L 30 D-55; EUDRAGIT® L100-55; EUDRAGIT® L 100; EUDRAGIT® L 12.5; EUDRAGIT® S 100; EUDRAGIT® S12.5; EUDRAGIT® FS 30 D; EUDRAGIT® E 100; EUDRAGIT® E 12.5; EUDRAGIT® EPO; EUDRAGIT® RL 100; EUDRAGIT® RL PO; EUDRAGIT® RL 30 D; EUDRAGIT® RL12.5; EUDRAGIT® RS 100; EUDRAGIT® RS PO; EUDRAGIT® RS 30 D; EUDRAGIT® RS12.5; EUDRAGIT® NE 30 D; EUDRAGIT® NE 40 D; EUDRAGIT® NM 30 D; or otherpoly(meth)acrylate polymers. In one aspect, the enteric polymer isEUDRAGIT® L 100, a methacrylic acid copolymer, Type A. Acid-insolublepolymer specifications are detailed in the United States Pharmacopoeiaand in various monographs. Without being bound by any theory, it isbelieved that the acid-insoluble properties of the gel mass andresulting capsule shell is derived from the intermolecular ionicinteractions between the positively charged Type-A gelatin and thenegatively charged anionic polysaccharide; thus, such formulationsobviate the need for any crosslinking or gelling agents. Acid-insolublespecifications of enteric capsules are detailed in the United StatesPharmacopoeia, which is incorporated by reference herein for suchteachings.

Useful plasticizers as described herein comprise glycerol, sorbitol,Sorbitol Special® (SPI Pharma), non-crystallizing sorbitol, Polysorb®sorbitol 85/70/00 (Roquette), maltitol, corn syrup, polyethylene glycol,1,2-propylene glycol, acetyltriethyl citrate, dibutyl phthalate, dibutylsebacate, triacetine, polydextrose, dextrose, maltodextrin, citric acid,citric acid esters, such as triethyl citrate, or combinations thereof.The weight ratio between the film-forming polymer, the entericacid-insoluble polymer, and plasticizer is adjusted so that the gel massis flowable and not too viscous, and can be made into soft capsulesusing rotary die encapsulation methods.

In one particular embodiment described herein, the plasticizer comprisesat least one of glycerol, sorbitol, or mixtures or combinations thereof.In one embodiment, optional gelling agents can be added to the entericsoft capsules. The addition of gelling agents is optional and depends onthe gelatin type (e.g., Type B gelatin), which may function to increasethe overall strength of the capsule shell. Without being bound to anytheory, it is believed that the cationic gelling agent promotes an ionicinteraction between the gelatin composition and the anionic entericpolymer. Suitable gelling agents as described herein comprise mono ordivalent cations, such as calcium, sodium, potassium, magnesium, ortheir salt forms comprising calcium sulfate, sodium chloride, potassiumsulfate, sodium carbonate, lithium chloride, sodium borate, potassiumbromide, potassium fluoride, sodium bicarbonate, calcium chloride,magnesium chloride, sodium citrate, sodium acetate, calcium lactate,magnesium sulfate, sodium fluoride, or mixtures thereof.

In one embodiment described herein, the all-natural enteric soft capsuleshell has the composition of Table 1, including all possible iterationsof the specified ranges that provide 100% for the total weightpercentage, including or excluding the optional colorings, flavorings,or excipients.

TABLE 1 All-natural Enteric Soft Capsule Shell Composition ExemplaryComposition Component Components Range (%) Gelatin Type A Gelatin or20-40 composition Type A Gelatin + (Type A: 25-37/Type B: Type B Gelatinor 32-37/Gel. Hydro: 28-36) Type A Gelatin + Gelatin Hydrolysate Entericanionic Anionic 2-7 polymer polysaccharide (e.g., pectin) PlasticizerGlycerol, Sorbitol,  8-30 Triethyl citrate Gelling agent Calcium,Magnesium, 0.001-0.05  Potassium Solvent Water 40-70 Opacifier(optional) Titanium dioxide 0.5-5   Coloring (optional) Various0.005-1    Flavoring (optional) Various 0.005-2    Excipients (optional)Various 1-5

In another embodiment described herein, the weight percentage of thetotal gelatin composition in the all-natural enteric soft capsulecomposition is about 25% to about 37% including all integers within thespecified range. In another embodiment, the weight percentage of thegelatin composition in the gel mass is about 32% to about 37% includingall integers within the specified range. In another embodiment, theweight percentage of the gelatin composition in the gel mass is about28% to about 36%. In one aspect, the weight percentage of the gelatincomposition in the gel mass is about 33%.

In another embodiment described herein, the weight percentage ratiorange of Type A gelatin to Type B gelatin in the all-natural entericsoft capsule composition is about 2:1 to about 11:1, including allratios within the specified range. In one aspect, the weight percentageratio range of Type A gelatin to Type B gelatin in the gel mass is about6:1. In another aspect, the ratio of Type A gelatin to Type B gelatin inthe gel mass is about 3:1.

In another embodiment described herein, the weight percentage ratio ofType A gelatin to gelatin hydrolysate in the all-natural enteric softcapsule composition is about 10:1 to about 35:1, including all ratioswithin the specified range. In one aspect, the weight percentage ratioof Type A gelatin to gelatin hydrolysate in the gel mass is about 12:1,including all integers within the specified range. In another aspect,the ratio of Type A gelatin to gelatin hydrolysate in the gel mass isabout 27:1.

In one embodiment described herein, all-natural enteric soft capsulecompositions comprising Type A gelatin in the all-natural enteric softcapsule gel mass are preferable to all-natural enteric soft capsulecompositions comprising Type A gelatin and Type B gelatin in theall-natural enteric soft capsule gel mass. In another embodimentdescribed herein, all-natural enteric soft capsule compositionscomprising Type A gelatin are preferable to all-natural enteric softcapsule compositions comprising Type A gelatin and gelatin hydrolysatein the all-natural enteric soft capsule gel mass. In one aspectdescribed herein, all-natural enteric soft capsule compositionsdescribed herein are comprised of Type A gelatin in the all-naturalenteric soft capsule gel mass.

In another embodiment described herein, the weight percentage of Type Agelatin in the all-natural enteric soft capsule composition is about 22%to about 38%, including all integers within the specified range. Inanother embodiment, the weight percentage of Type A gelatin in the gelmass is about 28% to about 36%, including all integers within thespecified range. In one aspect, the weight percentage of Type A gelatinin the gel mass is about 28%. In another aspect, the weight percentageof Type A gelatin in the gel mass is about 31%. In another aspect, theweight percentage of Type A gelatin in the gel mass is about 33%.

In another embodiment described herein, the weight percentage of Type Bgelatin in the all-natural enteric soft capsule composition is about0.01% to about 10%, including all integers within the specified range.In another embodiment, the weight percentage of Type B gelatin in thegel mass is about 0.01% to about 7%, including all integers within thespecified range. In one aspect, the weight percentage of Type B gelatinin the gel mass is about 3%. In another aspect, the weight percentage ofType B gelatin in the gel mass is about 7%. In another aspect, theweight percentage of Type B gelatin in the gel mass is about 9%.

In another embodiment described herein, the weight percentage range ofanionic polymer in the all-natural enteric soft capsule composition isabout 2% to about 7%, including all integers within the specified range.In one aspect, the weight percentage of anionic polymer in the gel massis about 2.8%. In another aspect, the weight percentage of anionicpolymer in the gel mass is about 3.1%. In another aspect, the weightpercentage of anionic polymer in the gel mass is about 3.3%. In anotheraspect, the weight percentage of anionic polymer in the gel mass isabout 5%. In another aspect, the weight percentage of anionic polymer inthe gel mass is about 6.8%.

In one embodiment described herein, the weight percentage range of totalionically bonded polymer content (i.e., total gelatin content andanionic polymer) of the enteric soft capsule composition describedherein is about 28% to about 41%, including all integers within thespecified range. In one aspect, the total ionically bonded polymerweight percentage in the gel mass is about 31%. In another aspect, thetotal ionically bonded polymer weight percentage in the gel mass isabout 35%. In another aspect, the total ionically bonded polymer weightpercentage in the gel mass is about 40%.

In another embodiment described herein, the weight percentage range oftotal plasticizer in the all-natural enteric soft capsule composition isabout 8% to about 20%, including all integers within the specifiedrange. In one aspect, the weight percentage of plasticizer in the gelmass is about 12%. In another aspect, the weight percentage ofplasticizer in the gel mass is about 14%. In another aspect, the weightpercentage of plasticizer in the gel mass is about 17%.

In another embodiment described herein, the weight percentage range ofgelling agent of the enteric soft capsule composition described hereinis about 0.001% to about 0.05%, including all integers within thespecified range. In one aspect, the weight percentage of the gellingagent in the gel mass is about 0.003%. In another aspect, the weightpercentage of the gelling agent in the gel mass is about 0.006%.

In one embodiment described herein, the weight percentage ratio range oftotal gelatin to anionic polymer of the enteric soft capsule compositiondescribed herein is about 4:1 to about 19:1, including all ratios withinthe specified range. In one aspect, the weight percentage ratio of totalgelatin to anionic polymer in the gel mass is about 4:1. In one aspect,the weight percentage ratio of total gelatin to anionic polymer in thegel mass is about 6:1. In one aspect, the weight percentage ratio oftotal gelatin to anionic polymer in the gel mass is about 10:1. In oneaspect, the weight percentage ratio of total gelatin to anionic polymerin the gel mass is about 12:1. In one aspect, the weight percentageratio of total gelatin to anionic polymer in the gel mass is about 15:1.In one aspect, the weight percentage ratio of total gelatin to anionicpolymer in the gel mass is about 19:1.

In one embodiment described herein, the weight percentage ratio range oftotal gelatin to plasticizer of the enteric soft capsule compositiondescribed herein is about 1.5:1 to about 4.5:1, including all ratioswithin the specified range. In one aspect, the weight percentage ratioof total gelatin to plasticizer in the gel mass is about 2:1. In oneaspect, the weight percentage ratio of total gelatin to plasticizer inthe gel mass is about 3:1. In one aspect, the weight percentage ratio oftotal gelatin to plasticizer in the gel mass is about 4:1.

In one embodiment described herein, the weight percentage ratio range ofplasticizer to anionic polymer of the enteric soft capsule compositiondescribed herein is about 2:1 to about 8:1, including all ratios withinthe specified range. In one aspect, the weight percentage ratio ofplasticizer to anionic polymer in the gel mass is about 3:1. In oneaspect, the weight percentage ratio of plasticizer to anionic polymer inthe gel mass is about 4:1. In one aspect, the weight percentage ratio ofplasticizer to anionic polymer in the gel mass is about 6:1. In oneaspect, the weight percentage ratio of plasticizer to anionic polymer inthe gel mass is about 8:1.

In one embodiment described herein, the solvent comprises about 40% toabout 70% of the wet enteric soft capsule composition, including allintegers within the specified range. In one aspect, the solvent iswater. The quantity of water in the composition varies depending on thequantities of the other ingredients. For example, the quantity ofopacifier, coloring, flavoring, or other excipients can change thepercentage of water present in the composition. In one embodiment, theweight percentage of water is as much as suffices to bring the totalweight percentage to 100% (i.e., quantum sufficiat; q.s.). In anotherembodiment, the water comprises about 60%, about 50%, or about 40%, ofthe wet enteric soft capsule composition. In another embodiment, watercomprises about 42% of the wet enteric soft capsule composition. Inanother embodiment, water comprises about 55% of the wet enteric softcapsule composition.

In one embodiment described herein, the final moisture (water) contentof the enteric soft capsule shell formed from the compositions describedherein is adequately adjusted prior to vacuum deaeration. In anotherembodiment, an additional 1% to about 10% by weight of water, includingall integers within the specified range, is added to the gel massadjusted prior to vacuum deaeration. In another embodiment, anadditional 1% to about 5% by weight of water, including all integerswithin the specified range, is added to the gel mass adjusted prior tovacuum deaeration. In one aspect, an additional 3% by weight of water isadded to the gel mass adjusted prior to vacuum deaeration.

In one aspect, the final moisture content of the enteric soft capsuleshell after vacuum deaeration and drying is from about 5% to about 25%including all integers within the specified range. In another aspect,the final moisture content of the enteric soft capsule shell aftervacuum deaeration and drying is from about 5% to about 16% including allintegers within the specified range. In another aspect, the finalmoisture content of the enteric soft capsule shell after vacuumdeaeration and drying is from about 8% to about 12% including allintegers within the specified range. In another aspect, the finalmoisture content of the enteric soft capsule shell after vacuumdeaeration and drying is about 5%. In another aspect, the final moisturecontent of the enteric soft capsule shell after vacuum deaeration anddrying is about 8%. In another aspect, the final moisture content of theenteric soft capsule shell after vacuum deaeration and drying is about12%. In another aspect, the final moisture content of the enteric softcapsule shell after vacuum deaeration and drying is about 13%. Inanother aspect, the final moisture content of the enteric soft capsuleshell after vacuum deaeration and drying is about 16%.

The relative percentages of the other components of the enteric softcapsule shell described herein (e.g., gelatin composition, anionicpolymer, plasticizers, and optional components such as flavorings,opacifiers, colorants and other excipients as described herein) can becalculated by the relative change in moisture content between the wetenteric soft capsule composition and the dried enteric soft capsulecomposition as manufactured by the methods described herein (e.g., thepercentages of the other components will only increase relative to eachother as moisture is removed unless they are fugitive, like ammonia).

In one embodiment described herein, the enteric soft capsule describedherein comprises a composition of about 33% gelatin composition; about3.3% enteric, acid insoluble anionic polymer; about 16% plasticizer; andabout 47% solvent.

In another embodiment described herein, an enteric soft capsule shellcan be made by using an aqueous dispersion of the acid-insoluble polymerby adding alkaline materials such as ammonium, sodium, or potassiumhydroxides, other alkalis, or a combination thereof that will cause theenteric acid-insoluble polymer to dissolve. The plasticizer-wetted,film-forming polymer can then be mixed with the solution of theacid-insoluble polymer. In one embodiment, enteric acid-insolublepolymers in the form of salts of the above-mentioned bases or alkaliscan be dissolved directly in water and mixed with theplasticizer-wetted, film-forming polymer.

In one embodiment, an enteric soft capsule shell has the composition ofTable 2, including all possible iterations of the specified ranges thatprovide 100% for the total weight percentage, including or excluding theoptional, excipients, opacifiers, colorants, and flavorings.

TABLE 2 Exemplary Enteric Soft Capsule Shell Composition ExemplaryComposition Component Component Range (%) Film-forming polymer Gelatin20-36 Enteric, acid Methacrylic  8-20 insoluble polymer Acid CopolymerPlasticizer Glycerol, Triethyl citrate 15-22 Alkali neutralizing agentsNH₄OH (30%), NaOH 1-5 Solvent Water 20-40 Opacifier Titanium Dioxide 1-7.5 Colorant (optional) Various 0.05-1   Flavoring (optional) Various0.05-2   Excipients (optional) Various 1-5

In one embodiment, an enteric soft capsule shell comprises a compositionof about 30% film forming polymer; about 10% enteric, acid insolublepolymer; about 20% plasticizer; about 1% alkali neutralizing agent; andabout 37% solvent.

In one embodiment, the weight percentage range of total polymer content(i.e., film forming polymer and enteric acid-insoluble polymer) of theenteric soft capsule described herein is about 30% to about 45%,including all integers within the specified range. In one aspect, thetotal polymer weight percentage is about 40%. In another aspect, thetotal polymer weight percentage is about 42%. In another aspect, thetotal polymer weight percentage is about 45%. In another aspect, thetotal polymer weight percentage is about 38%.

In one embodiment, the weight percentage range of total plasticizer isabout 15% to about 22%, including all iterations of integers with thespecified range. In one aspect, the total plasticizer weight percentageis about 19%. In another aspect, the total plasticizer weight percentageis about 17.7%. In another aspect, the total plasticizer weightpercentage is about 18.9%. In another aspect, the total plasticizerweight percentage is about 19.3%.

In one embodiment, the alkali neutralizing-agent is ammonia (ammoniumhydroxide; 30% w/v) that is added to comprise a weight percentage ofabout 1% to about 5% of the total enteric soft capsule composition. Inone aspect, 30% w/v ammonia is added to comprise a weight percentage ofabout 2%. In another aspect, 30% w/v ammonia is added to a weightpercentage of about 1.7%. In one aspect, ammonia is added to provide afinal pH of about 9 in the enteric soft capsule composition. In anotheraspect, ammonia is added to provide a final pH of about 8.5 in theenteric soft capsule composition. In another aspect, after the capsulesare filled and dried, the ammonia concentration is substantiallyreduced, owing to the fugitive nature of the volatile alkali. In oneaspect, practically all of the ammonia is evaporated except for ammoniumions comprising salts with other moieties in the composition.

In one embodiment, the weight ratio range of film forming polymer toenteric acid insoluble polymer (film forming: enteric) is about 25:75(≈0.33) to about 40:60 (≈0.67) (i.e., ≈0.33-0.67), including alliterations of ratios within the specified range. In one aspect, theratio of film forming polymer to enteric acid insoluble polymer is about30:70 (≈0.43). In another aspect, the ratio of film forming polymer toenteric acid insoluble polymer is about 28:72 (≈0.38).

In one embodiment, the weight ratio of total plasticizer to film formingpolymer is about 20:40 to 21:30 (i.e., ≈0.5-0.7), including alliterations of ratios within the specified range. In one aspect, theweight ratio of total plasticizer to film forming polymer is about 20:40(≈0.5). In another aspect, the weight ratio of total plasticizer to filmforming polymer is about 21:30 (≈0.7). In another aspect, the weightratio of total plasticizer to film forming polymer is about 19:29(≈0.65). In another aspect, the weight ratio of total plasticizer tofilm forming polymer is about 19.3:29.2 (≈0.66).

In one embodiment, the weight ratio of total plasticizer to enteric acidinsoluble polymer is about 1:1 to about 2:1 (≈1-2), including alliterations of ratios within the specified range. In one aspect, theweight ratio of total plasticizer to enteric acid insoluble polymer isabout 11:10 (≈1.1). In another aspect, the weight ratio of totalplasticizer to enteric acid insoluble polymer is about 14:10 (≈1.4). Inanother aspect, the weight ratio of total plasticizer to enteric acidinsoluble polymer is about 17:10 (≈1.7). In another aspect, the weightratio of total plasticizer to enteric acid insoluble polymer is about20:10 (≈2). In another aspect, the weight ratio of total plasticizer toenteric acid insoluble polymer is about 19.3:11.2 (≈1.73).

In one embodiment, the weight ratio range of total plasticizer to totalpolymer (film forming and enteric acid insoluble polymer) is about 18:45to about 20:40 (i.e., ≈0.40-0.5), including all iterations of ratioswithin the specified range. In one aspect, the weight ratio range oftotal plasticizer to total polymer is about 18:45 (≈0.40). In anotheraspect, the weight ratio range of total plasticizer to total polymer isabout 19:40 (≈0.475). In another aspect, the weight ratio range of totalplasticizer to total polymer is about 20:40 (≈0.5). In another aspect,the weight ratio range of total plasticizer to total polymer is about19.3:40.4 (≈0.477).

In one embodiment, the solvent comprises about 20% to about 40% of theenteric soft capsule composition, including all integers within thespecified range. In one embodiment, the solvent is water. The quantityof water in the composition varies depending on the quantities of theother ingredients. For example, the quantity of opacifier, colorant,flavoring, or other excipients can change the percentage of waterpresent in the composition. In one embodiment, the weight percentage ofwater is as much as suffices to bring the total weight percentage to100% (i.e., quantum sufficiat; q.s.). In another embodiment, the watercomprises about 20%, about 25%, about 30%, about 35%, or about 40% ofthe enteric soft capsule composition. In another embodiment, watercomprises about 35% to about 40% of the enteric soft capsulecomposition. In one embodiment, water comprises about 37% of thecomposition.

In one embodiment, the final moisture (water) content of the entericsoft capsule is from about 8% to about 15%, including all integerswithin the specified range. In another embodiment, the moisture contentis about 8% to about 12%, including all integers within the specifiedrange. In one aspect, the final moisture content is about 8%. In oneaspect, the final moisture content is about 9%. In one aspect, the finalmoisture content is about 10%. In one aspect, the final moisture contentis about 11%. In another aspect, the final moisture content is about12%.

In one embodiment, the enteric soft capsule shell has the exemplarycomposition shown in Table 3.

TABLE 3 Exemplary Enteric Soft Capsule Shell Composition ComponentPercent weight (%) Gelatin 29.2 Methacrylic Acid 11.2 Copolymer(EUDRAGIT ® L 100) Glycerol 18.0 Triethyl citrate  1.3 Ammoniumhydroxide  1.7 Titanium dioxide  1.5 Water 37.1 TOTAL 100% Final pH4.0-9.0 Total polymer % weight (gelatin + enteric) 40.4 Gelatin % wt oftotal polymer (gelatin + enteric) 72.4 Enteric % wt of total polymer(gelatin + enteric) 27.6 Ratio of Enteric to Gelatin 11.2:29.2 (0.38)Total plasticizer % weight 19.3 (glycerol + triethyl citrate) Ratio oftotal plasticizer to total polymer 19.3:40.4 (0.48) Ratio totalplasticizer to gelatin 19.3:29.2 (0.66) Ratio total plasticizer toenteric 19.3:11.2 (1.73) Water content in dried enteric soft capsule: 8-15

In one embodiment, the enteric soft capsule shell comprises about 30%gelatin; about 10% poly(methyl) acrylate copolymer; about 18% glycerol;about 1% triethyl citrate; about 1.5% ammonia; about 37% water; andabout 1.5% titanium dioxide.

One embodiment described herein provides an enteric acid-insolublepolymer dispersed within the film-forming polymer gel mass that providesthe total soft capsule composition with enteric acid-insolubleproperties, at relatively low concentrations of the entericacid-insoluble polymer (e.g., from about 8% to about 20% of the totalwet gel mass composition) and without the need of excessive amounts ofalkali, thus avoiding denaturation or degradation of the film-formingpolymer that can weaken the integrity of the enteric soft capsule shell.

In one embodiment described herein, soft capsules can be substituted forenteric soft capsules. In one embodiment described herein, thepharmaceutical composition comprises a soft capsule shell comprising amatrix fill further comprising an active pharmaceutical ingredient.

In one embodiment described herein, the soft capsule shell has thecomposition of Table 4, including all possible iterations of thespecified ranges that provide 100% for the total weight percentage,including or excluding the optional colorings, flavorings, orexcipients.

TABLE 4 Exemplary Soft Capsule Shell Composition Exemplary CompositionComponent Component Range (%) Film-forming polymer Gelatin 25-50Plasticizer Glycerol 15-25 Solvent Water 20-40 Opacifier (optional)Titanium dioxide 0.5-1.5 Coloring agent (optional) Various 0.05-0.1 

In one embodiment, the soft capsule shell has the exemplary compositionshown in Table 5.

TABLE 5 Exemplary Soft Capsule Shell Composition Component Percentweight (%) Gelatin 43 Glycerol 20 Titanium dioxide 0.7 Coloring agent0.1 Water 36.2 TOTAL 100% Final pH 4-7 Ratio total plasticizer togelatin 20:43 (0.46:1) Water content in dried soft capsule shell:  8-15

In one embodiment described herein, the soft capsule comprises about 43%of at least one film-forming polymer; about 20% of at least oneplasticizer; about 36% water; optionally, about 0.7% titanium dioxide;and optionally, about 0.1% of at least one coloring agent.

In one embodiment, the weight percentage range of film-forming polymerof the soft capsule described herein is about 35% to about 45%,including all integers within the specified range. In one aspect, thefilm-forming polymer weight percentage is about 38%. In another aspect,the film-forming polymer weight percentage is about 42%. In anotheraspect, the film-forming polymer weight percentage is about 44%.

In one embodiment, the weight percentage range of plasticizer is about15% to about 22%, including all iterations of integers with thespecified range. In one aspect, the plasticizer weight percentage isabout 17%. In another aspect, the plasticizer weight percentage is about18.5%. In another aspect, the plasticizer weight percentage is about20%.

In one embodiment, the weight percentage ratio range of plasticizer tofilm-forming polymer is about 0.33:1 to about 0.56:1, including alliterations of iterations of ratios with the specified range. In oneembodiment, the weight percentage ratio range of plasticizer tofilm-forming polymer is about 0.38:1. In one embodiment, the weightpercentage ratio range of plasticizer to film-forming polymer is about0.42:1. In one embodiment, the weight percentage ratio range ofplasticizer to film-forming polymer is about 0.46:1. In one embodiment,the weight percentage ratio range of plasticizer to film-forming polymeris about 0.52:1.

Natural colorings can be used to tint the enteric capsule shell.Suitable natural colorings included annatto, betanin, butterfly pea,caramel coloring, chlorophyllin, elderberry juice, lycopene, cochineal,pandan, paprika, turmeric, saffron, and other plant or vegetablecolorings.

In some embodiments, the enteric soft capsule shell does not dissolve ordisintegrate in acids, such as 0.1 N hydrochloric acid or simulatedgastric fluid (ca. pH 1.2), despite the fact that the majority of theshell ingredients (i.e., greater than 50%) normally dissolve in, or aremiscible with, acids. In some embodiments, the enteric soft capsulesmade using the compositions described herein remain intact inhydrochloric acid or simulated gastric fluid for at least two hours andthe capsules readily release their contents upon shifting the pH of thesolution to ca. 6.8, such as that of simulated intestinal fluid. In oneaspect, the enteric soft capsule is resistant to dissolution at about pH1.2 for at least about 2 hours. In another aspect, the enteric softcapsule begins dissolution at pH of about 6.8 within about 10 min.

In another embodiment, the final enteric capsule composition providesfilms of increased strength without substantially compromising filmelasticity. Moreover, films made from the enteric soft capsulecompositions as described herein can be sealed at normal temperaturerange typically used for making traditional soft capsules. In oneaspect, enteric soft capsules are made using a rotary die apparatus asdescribed in U.S. Pat. Nos. 5,459,983; 5,146,730; and 6,482,516, each ofwhich are incorporated by reference herein for such teachings.

In another embodiment, the enteric soft capsules described herein havecapsule burst strength of about 20 kg to about 60 kg including allintegers within the specified range. In one aspect, the enteric softcapsules described herein have a capsule burst strength of about 25 kg.In one aspect, the enteric soft capsules described herein have a capsuleburst strength of about 56 kg.

In another embodiment, the enteric soft capsules described herein havehigh speed cracking strength of about 20 kg to about 60 kg including allintegers within the specified range. In one aspect, the enteric softcapsules described herein have a capsule burst strength of about 22 kg.In one aspect, the enteric soft capsules described herein have a capsuleburst strength of about 54 kg.

In one embodiment, enteric soft capsule shell compositions can be madeby dissolving the enteric acid-insoluble polymer in an aqueous solutionof an alkali neutralizing agent such as ammonia, sodium hydroxide,potassium hydroxide, or liquid amines such as tri-ethanol amine orethylene diamine. The amount of alkali is adjusted to give a final pHvalue of the gel mass less than or equal to about pH 9.0. In oneembodiment, the final pH does not exceed 8.5. The volatile alkalineutralizing agent, ammonia is preferred. The film-forming polymer canthen be combined with the plasticizer and solvent and then blended withthe acid-insoluble gel to make a final homogeneous mix in aheat-controlled vessel and can be degassed by using vacuum. The fugitiveammonia evaporates during degassing. Using the foregoing process, thealkali concentrations do not require an additional step such as heatingor neutralizing with acid in order to neutralize the gel mass.

In another embodiment described herein, the pharmaceutical compositioncomprises an enteric soft capsule shell comprising a matrix fillcomprising an active pharmaceutical ingredient.

The enteric soft capsules or soft capsules described herein can containa matrix fill that is liquid, semi-solid, or solid. Capsules prepared asdescribed herein can contain a hydrophobic solution or suspension, suchas vegetable oils or shortening, soybean oils, or waxes, or combinationsthereof. The matrix fill can be formulated to prevent interaction withthe enteric soft capsule shell components and release the pharmaceuticalcomposition at a specified rate.

The fill can comprise one or more active ingredients and, optionally,one or more pharmaceutically acceptable excipients, colors, orflavorings.

Exemplary lipid or lipophilic liquid or semi-solid lipophilic substancesuseful for matrix fills include mineral oil; light mineral oil; naturaloils (e.g., vegetable, corn, canola, sunflower, soybean, olive, coconut,cocoa, peanut, almond, cottonseed, persic, sesame, squalane, castor, codliver, etc) hydrogenated vegetable oil; and partially hydrogenated oils;bees wax; polyethoxylated bee's wax; paraffin; normal waxes; mediumchain medium chain monoglycerides; diglycerides and triglycerides;higher aliphatic alcohols; higher aliphatic acids; long chain fattyacids; saturated or unsaturated fatty acids; hydrogenated fatty acids;fatty acid glycerides; polyoxyethylated oleic glycerides; monoglyceridesand diglycerides; mono-, bi- or tri-substituted glycerides; glycerolmono-oleate esters; glycerol mono-caprate; glyceryl monocaprylate;dicaprylate; monolaurate; glyceryl palmitostearate; glyceryl behenate;diethyleneglycol palmitostearate; polyethyleneglycol stearate;polyoxyethyleneglycol palmitostearate; glyceryl mono palmitostearate;cetyl palmitate; polyethyleneglycol palmitostearate;dimethylpolysiloxane; mono- or di-glyceryl behenate; fatty alcoholsassociated with polyethoxylate fatty alcohols; cetyl alcohol;octyldodecanol; myristyl alcohol; isopropyl myristate, isopropylpalmitate, stearic acid, stearyl alcohol, and others known in the art.

Additional solubility enhancing agents useful for the matrix fillsinclude Capmul® MCM, Captex® 355, Cremophor® RH 40, Croscarmellose,Crospovidone, Crospovidone CL, Crospovidone CL-F, Crospovidone CL-M,Imwitor® 742, Kollidon® CL, Kollidon® CL-F, Kollidon® CL-M, Labrafac™Lipophile WL 1349, Labrafil® M2125CS, Labrasol®, Lutrol® F 68, Maisine™35-1, mannitol, Miglyol® 812, Pearlitol® Flash, Peceol®, polyethyleneglycol 200, polyethylene glycol 400, polyethylene glycol 600,polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol2000, polyethylene glycol 3350, Plurol® Oleique CC 497, Povidone K 17,Povidone K 30, and sodium lauryl sulfate.

In one embodiment described herein, the enteric soft capsule or softcapsule matrix has the composition of Table 6, including all possibleiterations of the specified ranges that provide 100% for the totalweight percentage, including or excluding any optional colorings,flavorings, or excipients.

TABLE 6 Exemplary Soft Capsule Matrix Fill Formulation RangesComposition Ingredient Range (%) Wetting agent 0.5-5  Lipophilic liquid20-70 Semi-solid lipophilic substance 2-7 Hydrophilic polysaccharide 2-10 Hydrophilic polymer  2-10 Active pharmaceutical ingredient 20-60pH 6.0-9.0 TOTAL 100%

In one embodiment described herein, the enteric soft capsule or softcapsule matrix has the composition of Table 7, including all possibleiterations of the specified ranges that provide 100% for the totalweight percentage, including or excluding any optional colorings,flavorings, or excipients.

TABLE 7 Exemplary Soft Capsule Matrix Fill Formulation RangesComposition Ingredient Range (%) Solubility enhancing agent 10-85Solubilizing Plasticizer 2.5-10  Water 2.5-20  Active pharmaceuticalingredient  5-80 pH 6.0-9.0 TOTAL 100%

In one embodiment described herein, the matrix fill of thepharmaceutical composition comprises a wetting agent comprising fromabout 0.5% to about 5% of the matrix fill mass including all iterationsof integers within the specified range. In one aspect, the wetting agentcomprises about 0.5% of the matrix fill mass. In another aspect, thewetting agent comprises about 2% of the matrix fill mass. In anotheraspect, the wetting agent comprises about 3% of the matrix fill mass. Inone aspect, the wetting agent comprises about 4% of the matrix fillmass. In one aspect, the wetting agent comprises lecithin.

In one embodiment described herein, the matrix fill of thepharmaceutical composition comprises one or more lipophilic liquidscomprising from about 20% to about 70% of the matrix fill mass includingall iterations of integers within the specified range. In one aspect,the one or more lipophilic liquids comprises about 26% of the matrixfill mass. In another aspect, the one or more lipophilic liquidscomprises about 45% of the matrix fill mass. In another aspect, the oneor more lipophilic liquids comprises about 55% of the matrix fill mass.In another aspect, the one or more lipophilic liquids comprises about65% of the matrix fill mass. In another aspect, the one or morelipophilic liquids comprises vegetable oil and/or soybean oil.

In one embodiment described herein, the matrix fill of thepharmaceutical composition comprises a semi-solid lipophilic substancecomprising from about 2% to about 7% of the matrix fill mass includingall iterations of integers within the specified range. In one aspect,the semi-solid lipophilic substance comprises about 2% of the matrixfill mass. In another aspect, the semi-solid lipophilic substancecomprises about 3% of the matrix fill mass. In another aspect, thesemi-solid lipophilic substance comprises about 4% of the matrix fillmass. In another aspect, the semi-solid lipophilic substance comprisesabout 6% of the matrix fill mass. In another aspect, the semi-solidlipophilic substance comprises bee's wax.

In one embodiment described herein, the matrix fill of thepharmaceutical composition comprises a hydrophilic polysaccharidecomprising from about 2% to about 10% of the matrix fill mass includingall iterations of integers within the specified range. In one aspect,the hydrophilic polysaccharide comprises about 2% of the matrix fillmass. In another aspect, the hydrophilic polysaccharide comprises about4% of the matrix fill mass. In another aspect, the hydrophilicpolysaccharide comprises about 7% of the matrix fill mass. In anotheraspect, the hydrophilic polysaccharide comprises about 9% of the matrixfill mass. In another aspect, the hydrophilic polysaccharide compriseschitosan.

In one embodiment described herein, the matrix fill of thepharmaceutical composition comprises a hydrophilic polymer comprisingfrom about 2% to about 10% of the matrix fill mass including alliterations of integers within the specified range. In one aspect, thehydrophilic polymer comprises about 2% of the matrix fill mass. In oneaspect, the hydrophilic polymer comprises about 4% of the matrix fillmass. In one aspect, the hydrophilic polymer comprises about 7% of thematrix fill mass. In one aspect, the hydrophilic polymer comprises about9% of the matrix fill mass. In one aspect, the hydrophilic polymercomprises Carbopol® 971.

In one embodiment described herein, the matrix fill of thepharmaceutical composition comprises a wetting agent of about 1.5%, amixture of two lipophilic liquids of about 65%, a semi-solid lipophilicsubstance of about 3%, a hydrophilic polysaccharide of about 5%, ahydrophilic polymer of about 5%, and an active pharmaceutical ingredientof about 6% to about 20% including all iterations of integers within thespecified range. In one aspect, the matrix fill comprises an activepharmaceutical ingredient of about 6%. In another aspect, the matrixfill comprises an active pharmaceutical ingredient of about 20%.

In one embodiment described herein, the weight ratio range of one ormore lipophilic liquids to the semi-solid substance is about 5:1 toabout 25 to 1, including all ratios within the specified range. In oneaspect, the weight ratio of one or more lipophilic liquids to thesemi-solid substance is about 22 to 1.

In one embodiment described herein, the weight ratio range ofhydrophilic components (e.g., hydrophilic polysaccharide and hydrophilicsynthetic) to lipophilic components (e.g., lipophilic liquid andlipophilic semi-solid substance) is about 1:30 to about 1:2, includingall ratios within the specified range. In one aspect, the weight ratioof one or more hydrophilic polymers to lipophilic is about 1:7.

In one embodiment described herein, the weight ratio range of wettingagent to hydrophilic and lipophilic components is about 1:30 to about1:2, including all ratios within the specified range. In one aspect, theweight ratio of wetting agent to hydrophilic and lipophilic is about1:50.

In one embodiment described herein, the matrix fill of thepharmaceutical composition comprises a solubility enhancing agentcomprising from about 10% to about 35% of the matrix fill mass includingall iterations of integers within the specified range. In one aspect,the solubility enhancing agent comprises about 10% of the matrix fillmass. In another aspect, the solubility enhancing agent comprises about20% of the matrix fill mass. In another aspect, the solubility enhancingagent comprises about 35% of the matrix fill mass.

In another embodiment described herein, the solubility enhancing agentcomprises from about 45% to about 85% of the matrix fill mass includingall iterations of integers within the specified range. In one aspect,the solubility enhancing agent comprises about 45% of the matrix fillmass. In another aspect, the solubility enhancing agent comprises about65% of the matrix fill mass. In another aspect, the solubility enhancingagent comprises about 80% of the matrix fill mass.

In one embodiment, the solubility enhancing agent increases thesolubility of active pharmaceutical ingredients described herein. In oneaspect, the solubility enhancing agent increases the solubility ofdiclofenac potassium. In another aspect, the solubility enhancing agentcomprises polyethylene glycol 600. In another aspect, the solubilityenhancing agent comprises polyethylene glycol 400. In one aspect,polyethylene glycol 600 was unexpectedly superior to polyethylene glycol400 as a solubility enhancing agent.

In one embodiment described herein, the matrix fill of thepharmaceutical composition comprises a solubilizing plasticizercomprising from about 2.5% to about 10% of the matrix fill massincluding all iterations of integers within the specified range. In oneaspect, the solubilizing plasticizer comprises about 3% of the matrixfill mass. In another aspect, the solubilizing plasticizer comprisesabout 5% of the matrix fill mass. In another aspect, the solubilizingplasticizer comprises about 10% of the matrix fill mass.

In one embodiment, the solubilizing plasticizer comprises glycerol. Inanother embodiment, the solubilizing plasticizer comprises propyleneglycol. In another embodiment, propylene glycol is superior to glycerolas a solubilizing plasticizer.

In one embodiment described herein, the matrix fill of thepharmaceutical composition comprises a solubility enhancing agent ofabout 80%, a mixture of two lipophilic liquids of about 65%, asolubilizing plasticizer of about 5%, water content of about 5%, and anactive pharmaceutical ingredient of about 11% to about 40% including alliterations of integers within the specified range. In one aspect, thematrix fill comprises an active pharmaceutical ingredient of about 6%.In another aspect, the matrix fill comprises an active pharmaceuticalingredient of about 11%. In another aspect, the matrix fill comprises anactive pharmaceutical ingredient of about 30%. In another aspect, thematrix fill comprises an active pharmaceutical ingredient of about 35%.

In one embodiment, the matrix fill is comprised ofthe soft capsuleshells described herein. Without being bound by any theory, it isbelieved that water migrates from the soft capsule shells describedherein into the matrix fill described herein. In another aspect, thewater content of the matrix fill is increased by about 3% to about 15%by the migration of water from the shell to the fill.

In one embodiment described herein, the weight ratio range of solubilityenhancing agent to solubilizing plasticizer is about 2:1 to about 40:1,including all ratios within the specified range. In one aspect, theweight ratio of solubility enhancing agent to solubilizing plasticizeris about 16:1.

In one embodiment described herein, the weight ratio range of solubilityenhancing agent to water is about 2:1 to about 40:1, including allratios within the specified range. In one aspect, the weight ratio ofsolubility enhancing agent to water is about 16:1.

In one embodiment described herein, the weight ratio range ofsolubilizing plasticizer to water is about 1:2 to about 2:1, includingall ratios within the specified range. In one aspect, the weight ratioof wetting agent to hydrophilic and lipophilic is about 1:1.

In one embodiment described herein, the weight ratio range of activepharmaceutical ingredient to solubility enhancing agent is about 1:17 toabout 8:1, including all ratios within the specified range. In oneaspect, the weight ratio of active pharmaceutical ingredient tohydrophilic components is about 1:7. In another embodiment describedherein, the weight ratio range of active pharmaceutical ingredient tosolubilizing plasticizer is about 1:1 to about 16:1, including allratios within the specified range. In one aspect, the weight ratio ofactive pharmaceutical ingredient to lipophilic components is about 2:1.In another embodiment described herein, the weight ratio range of activepharmaceutical ingredient to water is about 1:1 to about 16:1, includingall ratios within the specified range. In one aspect, the weight ratioof active pharmaceutical ingredient to wetting agent is about 2:1.

The matrix fill can optionally include one or more pharmaceuticallyacceptable excipients. Examples of pharmaceutically acceptableexcipients include buffers, such as phosphate buffers, citrate buffer,and buffers with other organic acids; antioxidants including ascorbicacid; low molecular weight (less than about 10 residues) polypeptides;proteins, such as serum albumin, gelatin, or immunoglobulins;hydrophilic polymers, such as polyvinyl pyrrolidone; amino acids such asglycine, glutamine, asparagine, arginine or lysine; monosaccharides,disaccharides, and other carbohydrates, including glucose, mannose, ordextrins; chelating agents, such as EDTA; sugar alcohols, such asmannitol or sorbitol; salt-forming counterions, such as sodium; and/ornonionic surfactants, such as TWEEN® (ICI, Inc.; Bridgewater, N.J.), andPLURONICS™ (BASF; Florham Park, N.J.). Diluents commonly used in the artcan also be encapsulated within the shell, including water or othersolvents, solubilizing agents, and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, 1,3-butylene glycol, dimethylformamide, oils,in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil,castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, and fattyacid esters of sorbitan, and mixtures of these substances.

Additional pharmaceutical excipients useful for matrix fills include,for example, the following: Acidifying agents (acetic acid, glacialacetic acid, citric acid, fumaric acid, hydrochloric acid, dilutedhydrochloric acid, malic acid, nitric acid, phosphoric acid, dilutedphosphoric acid, sulfuric acid, tartaric acid); Alkalizing agents(ammonia solution, ammonium carbonate, diethanolamine,diisopropanolamine, potassium hydroxide, sodium bicarbonate, sodiumborate, sodium carbonate, sodium hydroxide, trolamine); Antifoamingagents (dimethicone, simethicone); Antimicrobial preservatives(benzalkonium chloride, benzalkonium chloride solution, benzethoniumchloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridiniumchloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid,ethylparaben, methylparaben, methylparaben sodium, phenol, phenylethylalcohol, phenylmercuric acetate, phenylmercuric nitrate, potassiumbenzoate, potassium sorbate, propylparaben, propylparaben sodium, sodiumbenzoate, sodium dehydroacetate, sodium propionate, sorbic acid,thimerosal, thymol); Antioxidants (ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorousacid, monothioglycerol, propyl gallate, sodium formaldehyde sulfoxylate,sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol,tocopherols excipient); Buffering agents (acetic acid, ammoniumcarbonate, ammonium phosphate, boric acid, citric acid, lactic acid,phosphoric acid, potassium citrate, potassium metaphosphate, potassiumphosphate monobasic, sodium acetate, sodium citrate, sodium lactatesolution, dibasic sodium phosphate, monobasic sodium phosphate);Chelating agents (edetate disodium, ethylenediaminetetraacetic acid andsalts, edetic acid); Coating agents (sodium carboxymethylcellulose,cellulose acetate, cellulose acetate phthalate, ethylcellulose, gelatin,pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxypropyl methylcellulose phthalate, methacrylicacid copolymer, methylcellulose, polyvinyl acetate phthalate, shellac,sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein);Colorants (caramel, red, yellow, black or blends, ferric oxide);Complexing agents (ethylenediaminetetraacetic acid and salts (EDTA),edetic acid, gentisic acid ethanolamide, oxyquinoline sulfate);Desiccants (calcium chloride, calcium sulfate, silicon dioxide);Emulsifying and/or solubilizing agents (acacia, cholesterol,diethanolamine (adjunct), glyceryl monostearate, lanolin alcohols, mono-and di-glycerides, monoethanolamine (adjunct), lecithin, oleic acid(adjunct), oleyl alcohol (stabilizer), poloxamer, polyoxyethylene 50stearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil,polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate80, diacetate, monostearate, sodium lauryl sulfate, sodium stearate,sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate,sorbitan monostearate, stearic acid, trolamine, emulsifying wax);Filtering aids (powdered cellulose, purified siliceous earth); Flavorsand perfumes (anethole, benzaldehyde, ethyl vanillin, menthol, methylsalicylate, monosodium glutamate, orange flower oil, peppermint,peppermint oil, peppermint spirit, rose oil, stronger rose water,thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin);Humectants (glycerin, hexylene glycol, sorbitol); Plasticizers (e.g.,castor oil, diacetylated monoglycerides, diethyl phthalate, glycerin,mono- and di-acetylated monoglycerides, propylene glycol, triacetin,triethyl citrate); Polymers (e.g., cellulose acetate, alkyl celluloses,hydroxyalkyl, acrylic polymers and copolymers); Solvents (acetone,alcohol, diluted alcohol, amylene hydrate, benzyl benzoate, butylalcohol, carbon tetrachloride, chloroform, corn oil, cottonseed oil,ethyl acetate, glycerin, hexylene glycol, isopropyl alcohol, methylalcohol, methylene chloride, methyl isobutyl ketone, mineral oil, peanutoil, propylene carbonate, sesame oil, water for injection, sterile waterfor injection, sterile water for irrigation, purified water); Sorbents(powdered cellulose, charcoal, purified siliceous earth); Carbon dioxidesorbents (barium hydroxide lime, soda lime); Stiffening agents(hydrogenated castor oil, cetostearyl alcohol, cetyl alcohol, cetylesters wax, hard fat, paraffin, polyethylene excipient, stearyl alcohol,emulsifying wax, white wax, yellow wax); Suspending and/orviscosity-increasing agents (acacia, agar, alginic acid, aluminummonostearate, bentonite, purified bentonite, magma bentonite, carbomer,carboxymethylcellulose calcium, carboxymethylcellulose sodium,carboxymethylcellulose sodium 12, carrageenan, microcrystalline andcarboxymethylcellulose sodium cellulose, dextrin, gelatin, guar gum,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, methylcellulose, pectin,polyethylene oxide, polyvinyl alcohol, povidone, alginate, silicondioxide, colloidal silicon dioxide, sodium alginate, tragacanth, xanthangum); Sweetening agents (aspartame, dextrates, dextrose, excipientdextrose, fructose, mannitol, saccharin, calcium saccharin, sodiumsaccharin, sorbitol, solution sorbitol, sucrose, compressible sugar,confectioner's sugar, syrup); Tablet binders (acacia, alginic acid,sodium carboxymethylcellulose, microcrystalline cellulose, dextrin,ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, povidone,pregelatinized starch, syrup); Tablet and/or capsule diluents (calciumcarbonate, dibasic calcium phosphate, tribasic calcium phosphate,calcium sulfate, microcrystalline cellulose, powdered cellulose,dextrates, dextrin, dextrose excipient, fructose, kaolin, lactose,mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressiblesugar, confectioner's sugar); Tablet disintegrants (alginic acid,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, starch, pregelatinizedstarch); Tablet and/or capsule lubricants (calcium stearate, glycerylbehenate, magnesium stearate, light mineral oil, sodium stearylfumarate, stearic acid, purified stearic acid, talc, hydrogenatedvegetable oil, zinc stearate); Tonicity agent (dextrose, glycerin,mannitol, potassium chloride, sodium chloride); Vehicle: flavored and/orsweetened (aromatic elixir, compound benzaldehyde elixir, iso-alcoholicelixir, peppermint water, sorbitol solution, syrup, tolu balsam syrup);Vehicle: oleaginous (almond oil, corn oil, cottonseed oil, ethyl oleate,isopropyl myristate, isopropyl palmitate, mineral oil, light mineraloil, myristyl alcohol, octyldodecanol, olive oil, peanut oil, persicoil, sesame oil, soybean oil, squalane); Vehicle: solid carrier (sugarspheres); Vehicle: sterile (Bacteriostatic water for injection,bacteriostatic sodium chloride injection); Viscosity-increasing (seesuspending agent); Water repelling agent (cyclomethicone, dimethicone,simethicone); and/or solubilizing agent (benzalkonium chloride,benzethonium chloride, cetylpyridinium chloride, docusate sodium,nonoxynol 9, nonoxynol 10, octoxynol 9, poloxamer, polyoxyl 35 castoroil, polyoxyl 40, hydrogenated castor oil, polyoxyl 50 stearate,polyoxyl 10 oleyl ether, polyoxyl 20, cetostearyl ether, polyoxyl 40stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate80, sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate,sorbitan monopalmitate, sorbitan monostearate, tyloxapol). This list isnot meant to be exclusive, but instead merely representative of theclasses of excipients and the particular excipients that may be used inoral dosage forms as described herein.

In one embodiment, the matrix fill can include a release regulator suchas a fatty acid salt, fatty acid ester, or fatty acid polyoxyethylenederivative. The release regulator can also be a surfactant having ahydrophilic/lipophilic balance (HLB) value between about 2 and about 40.The HLB characteristic of surfactants can be determined in accordancewith Physical Pharmacy: Physical Chemical Principles in thePharmaceutical Sciences, 4^(th) ed., 371-373, A. Martin, Ed., LippincottWilliams & Wilkins, Philadelphia (1993), which is incorporated byreference herein for such teachings.

In one embodiment, the matrix fill may include one or more hydrophiliccarriers. Examples of hydrophilic carriers are all natural, synthetic,or semi-synthetic products, which can be defined as aqueous carriers notmixable or only partially mixable with oil. All components can be usedalone or if possible in mixtures with different percentages. Amongaqueous components which can be used as a dispersing phase or also as adispersed phase.

Examples of aqueous solutions of hydrophilic polymers, which arehydrosoluble or hydrodispersable of various nature, such aspolyethylenglycol, polyvinyl pyrrolidone, polyacrylic acids andderivatives, such as Carbopol® 971, polymethacrylic acidspolyoxyethylenepolyoxypropylene copolymers (for example Poloxamer®,Lutrol™), hydrophilic polysaccharides of various nature, for exampledextran, xanthan, scleroglucan, arabic gum, guar gum, chitosan,cellulose and starch derivatives.

In one embodiment, the matrix fill can include a neutralizing agent.Without being bound to any theory, the neutralizing agent is thought tostabilize the active pharmaceutical ingredient in the matrix fill bypreventing hydrolysis. In addition, without being bound by any theory,it is also thought that the neutralizing agent stabilizes the entericsoft capsule shell by forming salts with the methylacrylate moietiesfrom the enteric soft capsule shell. In one aspect, the neutralizingagent comprises an organic acid, ester, or salt. In another aspect, theneutralizing agent comprises at least one of lactate, fumarate,caprylate, caprate, oleate, maleate, succinate, tartrate, citrate,glutamate, gluconate, esters or salts thereof, or combinations thereof.

In one embodiment, the matrix fill can include a hydrophilic internalphase and a lipid or lipophilic external phase. The internal phase ofthe matrix fill can include a plasticizer, such as propylene glycol, ora solubility enhancing agent, such as polyethylene glycol of molecularmass ranging from about 200 g/mol to about 8000 g/mol. In anotherembodiment, the internal phase can include hydroalcoholic solutions ofcellulose derivatives, hydrophilic polymers, polyacrylates, polyacrylicacids and derivatives (e.g., Carbopol™) polyvinyl polymers, chitosan orcombinations thereof.

In another embodiment, the internal phase of the matrix fill can includepolymers, such as methylcellulose, hydroxypropylmethylcellulose,polymethylmethacrylate, or polyvinylpyrrolidone (PVP). The internalphase of the matrix fill can also be structured. A “structured” internalphase of the matrix fill, as used herein, means a solid, semisolid, or agel whose shape is relatively stable and does not usually aggregate toform a large globule. A structured internal phase of the matrix filltherefore provides controlled drug release and stabilizes the physicalstate of the matrix. Without being bound by any theory, it is believedthat the structured nature of the matrix fill impedes solvation and/ordiffusion of the active pharmaceutical ingredient out of the matrixfill. In another embodiment, the external phase of the matrix fill caninclude a vegetable oil, hydrogenated vegetable oil (includingshortening), fatty acids, fatty acid esters, wax, bee's wax, soybeanoil, or a combination thereof. In another embodiment, an activepharmaceutical ingredient can be dispersed in the internal phase of thematrix fill as a suspension form.

In one embodiment, the matrix fill is a liquid (e.g., a solution,suspension, or dispersion) or a semisolid (e.g., a paste or gel). In oneaspect, the active pharmaceutical ingredient can be innately a liquid orsemisolid. In another aspect, the active ingredient can be prepared as aliquid or semisolid by, for example, by dissolving or otherwise mixingan active ingredient and optionally one or more pharmaceutical adjuvantsin a carrier, such as, for example, water, saline, aqueous dextrose,glycerol, glycols (e.g., propylene glycol), ethanol, fatty acids,glycerides, oils, sterols, phospholipids, and the like, to thereby forma solution.

In one embodiment described herein, the matrix fill comprises a lipid orlipophilic vehicle that provides a suspension of an activepharmaceutical ingredient having defined sizes. In one aspect, anenteric soft capsule comprising a suspension of an active pharmaceuticalingredient provides delayed release delivery of the activepharmaceutical ingredient.

In one embodiment described herein, the pharmaceutical compositionprovides matrix fills for an active pharmaceutical ingredient, orderivatives thereof, based on lipids or lipophilic materials. Thedescribed matrices have a hydrophobic (lipophilic) surface in contactwith a hydrophilic soft enteric capsule shell to minimize any potentialshell-fill interactions, such as when the enteric soft capsules arefilled with hydrophilic materials.

Examples of active pharmaceutical ingredients that can be includedcomprise agents classified as, for example, an adrenocortical steroid,adrenocortical suppressant, aldosterone antagonist, amino acid, anabolicsteroid, androgen, antagonist, anthelmintic, anti-acne agent,anti-adrenergic, anti-allergic, anti-amebic, anti-androgen, anti-anemic,anti-anginal, anti-arthritic, anti-asthmatic, anti-atherosclerotic,antibacterial, anticholelithic, anticholelithogenic, anticholinergic,anticoagulant, anticoccidal, antidiabetic, antidiarrheal, antidiuretic,antidote, anti-estrogen, antifibrinolytic, antifungal, antiglaucomaagent, antihemophilic, antihemorrhagic, antihistamine,antihyperlipidemic, antihyperlipoproteinemic, antihypertensive,antihypotensive, anti-infective, anti-infective, anti-inflammatory,antikeratinizing agent, antimalarial, antimicrobial, antimitotic,antimycotic, antineoplastic, antineutropenic, antiparasitic,antiperistaltic, antipneumocystic, antiproliferative, antiprostatichypertrophy, antiprotozoal, antipruritic, antipsoriatic, antirheumatic,antischistosomal, anti seborrheic, anti secretory, antispasmodic,antithrombotic, antitussive, anti-ulcerative, anti-urolithic, antiviral,appetite suppressant, benign prostatic hyperplasia therapy agent, boneresorption inhibitor, bronchodilator, carbonic anhydrase inhibitor,cardiac depressant, cardioprotectant, cardiotonic, cardiovascular agent,choleretic, cholinergic, cholinergic agonist, cholinesterasedeactivator, coccidiostat, contrasting agent, diagnostic aid, diuretic,ectoparasiticide, enzyme inhibitor, estrogen, fibrinolytic, free oxygenradical scavenger, glucocorticoid, gonad-stimulating principle, hairgrowth stimulant, hemostatic, hormone, hypocholesterolemic,hypoglycemic, hypolipidemic, hypotensive, imaging agent, immunizingagent, immunomodulator, immunoregulator, immunostimulant,immunosuppressant, impotence therapy adjunct, inhibitor, keratolytic,LHRH agonist, liver disorder treatment, luteolysin, mucolytic,mydriatic, nasal decongestant, neuromuscular blocking agent,non-hormonal sterol derivative, nonsteroidal anti-inflammatory drugs,oxytocic, plasminogen activator, platelet activating factor antagonist,platelet aggregation inhibitor, potentiator, progestin, prostaglandin,prostate growth inhibitor, prothyrotropin, radioactive agent, regulator,relaxant, repartitioning agent, scabicide, sclerosing agent, selectiveadenosine A1 antagonist, steroid, suppressant, symptomatic multiplesclerosis, synergist, thyroid hormone, thyroid inhibitor, thyromimetic,amyotrophic lateral sclerosis agents, Paget's disease agents, unstableangina agents, uricosuric, vasoconstrictor, vasodilator, vulnerary,wound healing agent, and xanthine oxidase inhibitor. Further examples ofsuitable pharmaceutical ingredients include those as listed in the MerckIndex (13^(th) Edition, Wiley, 2001), The United StatesPharmacopeia-National Formulary (USP-NF), and the FDA's Orange book,which are each incorporated by reference herein for their teachings ofpharmaceutically active ingredients.

Examples of nutraceuticals include, but are not limited to, amino acids,terpenoids (e.g., carotenoid terpenoids and non-carotenoid terpenoids),herbal supplements, homeopathic supplements, glandular supplements,polyphenolics, flavonoid polyphenolics, phenolic acids, curcumin,resveratrol, lignans, glucosinolates, isothiocyanates, indoles,thiosulfinates, phytosterols, anthraquinones, capsaicin, piperine,chlorophyll, betaine, oxalic acid, acetyl-L-carnitine, allantoin,androstenediol, androstendione, betaine (trimethylglycine), caffeine,calcium pyruvate (pyruvic acid), carnitine, carnosine, carotene,carotenoid, choline, chlorogenic acid, cholic acid, chondroitin sulfate,chondroitin sulfate, cholestan, chrysin, coenzyme Q10, conjugatedlinoleic acid, corosolic acid, creatine, dehydroepiandrosterone,dichlorophen, diindolymethane, dimethylglycine, dimercapto succinicacid, ebselen, ellagic acid, enzymes, fisetin, formononetin, glucaricacid (glucarate), glucosamine (HCl or sulfate), glucosamine (N-acetyl),glutathione, hesperidine, hydroxy-3-methylbutyric acid,5-hydroxytryptophan, indole-3-carbinol, inositol, isothiocyanates,linolenic acid-gamma, lipoic acid (alpha), melatonin,methylsulfonylmethane, minerals, naringin, pancreatin, para-aminobenzoicacid, paraben (methyl or propyl), phenolics, phosphatidylcholine,phosphatidylserine, phospholipids, phytosterols, progesterone,pregnenolone, omega-3 fatty acids, quercetin, resveratrol, D-ribose,rutin, S-adenosylmethionine, salicylic acid, sulforaphane, tartaricacid, taxifolin, tetrahydropalmatine, theophyline, theobromine,tigogenin, troxerutin, tryptophan, tocotrienol (alpha, beta, and gamma),zeaxanthin, gingko biloba, ginger, cat's claw, hypericum, aloe vera,evening primrose, garlic, capsicum, dong quai, ginseng, feverfew,fenugreek, echinacea, green tea, marshmallow, saw palmetto, tea treeoil, fish oil, psyllium, kava-kava, licorice root, mahonia aquifolium,hawthorne, yohimbe, tumeric, witch Hazel, valerian, mistletoe, bilberry,bee pollen, peppermint oil, beta-carotene, genistein, lutein, lycopene,the polyphenols, and the like. Further examples of suitablenutraceuticals include those listed in Handbook of Nutraceuticals andFunctional Foods, Robert E. C. Wildman, Ed., CRC Press (2001), which isincorporated by reference herein for the teachings related tonutraceuticals.

Examples of non-steroidal anti-inflammatory drugs (NSAID) compriseaceclofenac, acemetacin, aloxiprin, aspirin, azapropazone, benorilate,bromfenac, carprofen, celecoxib, choline magnesium salicylate,diclofenac, diflunisal, etodolac, etoricoxib, faislamine, fenbufen,fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac,lornoxicam, loxoprofen, meloxicam, meclofenamic acid, mefenamic acid,meloxicam, metamizole, methyl salicylate, magnesium salicylate,nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib,phenylbutazone, piroxicam, salicyl salicylate, sulindac, sulfinpyrazone,suprofen, tenoxicam, tiaprofenic acid, tolmetin, or valdecoxib.

Other useful pharmaceutical ingredients or nutraceuticals that can beincluded as an active ingredient include fish oils, egg oils, squidoils, krill oils, nut oils, seed oils; soy oils, avocado oils,seabuckthorn seed or berry oils, clary sage seed oils, algal oils,flaxseed oils, sacha ichi oils, echium oils, hemp oils, omega-3 fattyacids, polyunsaturated omega-3 fatty acids, hexadecatrienoic acid (HTA),alpha-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid(ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA,timnodonic acid), heneicosapentaenoic acid (HPA), docosapentaenoic acid(DPA), clupanodonic acid), docosahexaenoic acid (DHA, cervonic acid),tetracosapentaenoic acid, tetracosahexaenoic acid (nisinic acid), andfree acids, etheyl esters, or other esters or salts thereof. In oneaspect, the pharmaceutical ingredient is a highly purified omega-3 fattyacid, ester, or salt thereof.

Vitamins are nutraceuticals or pharmaceutical ingredients that includeorganic substances that are typically considered essential for thenormal growth and activity of a subject (e.g., a human or non-humananimal patient to whom the composition is to be administered). Examplesof vitamins include, but are not limited to vitamin A (retinol), B1(thiamine), B2 (riboflavin), B complex, B6 (pyridoxine), B12(cobalamin), C (ascorbic acid), D (cholecalciferol), E (tocopherol), F(linoleic acid), G, H (biotin), and K, and choline, folic acid,inositol, niacin, pantothenic acid, and para-aminobenzoic acid.

Vitamins can also include naturally occurring inorganic substances thatare typically considered essential for the normal growth and activity ofa subject (e.g., a human or non-human animal patient to whom thecomposition is to be administered). Examples of minerals include, butare not limited to, boron, calcium, chromium, copper, iron, magnesium,manganese, molybdenum, nickel, phosphorus, selenium, silicon, tin,vanadium, and zinc.

In one embodiment described herein, an active pharmaceutical ingredientis the only active ingredient in the pharmaceutical composition. Inanother embodiment, the active ingredient or drug can be an activepharmaceutical ingredient, derivatives thereof, or combinations thereof.

In one embodiment, the pharmaceutical compositions as described hereinare suitable for use for water soluble as well as slightly soluble orinsoluble active drug substances.

In another embodiment, the pharmaceutical compositions described hereinmay comprise pharmaceutically acceptable salts of any of the abovementioned active drug substances. The term “pharmaceutically acceptablesalts” of an active pharmaceutical ingredient includes alkali metalsalts such as, for example, sodium or potassium salts, alkaline earthmetal salts such as, for example, calcium and magnesium salts, and saltswith organic or inorganic acid such as, for example, hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citricacid, formic acid, maleic acid, succinic acid, tartaric acid,methanesulphonic acid, toluenesulphonic acid etc. In another embodiment,the active pharmaceutical ingredient may also be in the form ofpharmaceutically acceptable salts, uncharged or charged molecules,molecular complexes, solvates, or anhydrates thereof, and, if relevant,single isomers, enantiomers, racemic mixtures, or mixtures thereof.

In another embodiment, the active pharmaceutical ingredient may be inany of its crystalline, polymorphous, semi-crystalline, amorphous orpolyamorphous forms or mixtures thereof.

In one embodiment described herein, the ratio of the active ingredientor drug to the total matrix fill, e.g., matrix fill ingredient(s) andactive pharmaceutical ingredient(s), can be from about 1:50 to about 1:1by weight, including all ratios in the specified range. In anotherembodiment described herein, the active ingredient to total matrix fillratio can also be from about 1:16 to about 1:1 by weight, including allratios in the specified range. The active ingredient to total matrixfill ratio can also be about 1:16; about 1:9; about 1:3; about 1:2; orabout 1:1 including all ratios in the specified range.

In one embodiment described herein, the active ingredient or drugcomprises from about 5% to about 80% of the matrix fill mass includingall iterations of integers within the specified range. In one aspectdescribed herein, the active ingredient or drug comprises about 80% ofthe matrix fill mass. In another aspect, the active ingredient or drugcomprises about 60% of the matrix fill mass. In another aspect, theactive ingredient or drug comprises about 40% of the matrix fill mass.In another aspect, the active ingredient or drug comprises about 6% ofthe matrix fill mass.

In another embodiment described herein, the active ingredient or drugcomprises about 80%, about 70%, about 60%, about 50%, about 40%, about30%, about 20%, about 15%, about 10%, about 5%, about 2%, or about 1% ofthe matrix fill mass.

In one embodiment described herein, the weight ratio range of the activepharmaceutical ingredient to the matrix fill mass is about 1:20 to about10:1. In one aspect, the weight ratio of the active pharmaceuticalingredient to the matrix fill mass is about 1:3. In another aspect, theweight ratio of the active pharmaceutical ingredient to the matrix fillmass is about 1:9. In another aspect, the weight ratio of the activepharmaceutical ingredient to the matrix fill mass is about 1:17.

In one embodiment, the composition described herein can provide a dosageof an active ingredient for administration. The dosage form can beadministered, for example, to a subject, or a subject in need thereof.In one aspect, the subject may be a mammal, or a mammal in need thereof.In another aspect, the dosage form can be administered, for example, toa human or a human in need thereof. In another aspect, the human subjector a human subject in need thereof is a medical patient.

In one embodiment, the pharmaceutical composition described herein,comprises an active pharmaceutical ingredient of about 10 mg to about500 mg.

In one embodiment, the pharmaceutical composition described herein,comprises an active pharmaceutical ingredient of about 10 mg, about 20mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg,about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg,about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg,about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg,about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg,about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg,about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg,about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg,about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg,about 480 mg, about 490 mg, about 500 mg, or even more.

In one embodiment, the pharmaceutical composition described herein,comprises an active pharmaceutical ingredient of about 20 mg to about250 mg including all iterations of integers within the specified range.

In another embodiment, the pharmaceutical composition described herein,comprises an active pharmaceutical ingredient in the range of about 20mg to about 250 mg, about 30 mg to about 250 mg, about 40 mg to about250 mg, about 50 mg to about 250 mg, about 60 mg to about 250 mg, about70 mg to about 250 mg, about 80 mg to about 250 mg, about 90 mg to about250 mg, about 100 mg to about 250 mg, about 110 mg to about 250 mg,about 120 mg to about 250 mg, about 130 mg to about 250 mg, about 140 mgto about 250 mg, about 150 mg to about 250 mg, about 160 mg to about 250mg, about 170 mg to about 250 mg, about 180 mg to about 250 mg, about190 mg to about 250 mg, about 200 mg to about 250 mg, about 210 mg toabout 250 mg, about 220 mg to about 250 mg, about 230 mg to about 250mg, or about 240 mg to about 250 mg, including all iterations ofintegers within the specified ranges above.

In one embodiment described herein, the soft capsules described hereincomprise an active pharmaceutical ingredient comprising diclofenac or apharmaceutically acceptable salt form thereof, including but not limitedto diclofenac sodium, diclofenac potassium, or diclofenac hydrochloride.In another embodiment, diclofenac is present in its free acid form. Asused herein, “diclofenac” refers to all possible salt forms of theactive pharmaceutical ingredient if a particular salt is not specified.

In one embodiment described herein, the dose of diclofenac is about 10mg to about 500 mg, including all integers within the specified range.In one aspect, the dose of diclofenac is about 10 mg. In another aspect,the dose of diclofenac is about 12.5 mg. In another aspect, the dose ofdiclofenac is about 25 mg. In another aspect, the dose of diclofenac isabout 50 mg. In another aspect, the dose of diclofenac is about 75 mg.In another aspect, the dose of diclofenac is about 100 mg. In anotheraspect, the dose of diclofenac is about 125 mg. In another aspect, thedose of diclofenac is about 150 mg. In another aspect, the dose ofdiclofenac is about 175 mg. In another aspect, the dose of diclofenac isabout 200 mg. In another aspect, the dose of diclofenac is about 225 mg.In another aspect, the dose of diclofenac is about 250 mg. In anotheraspect, the dose of diclofenac is about 300 mg. In another aspect, thedose of diclofenac is about 350 mg. In another aspect, the dose ofdiclofenac is about 400 mg. In another aspect, the dose of diclofenac isabout 450 mg. In another aspect, the dose of diclofenac is about 500 mg.

The concentration of the active pharmaceutical ingredient in thepharmaceutical composition depends on the specific active pharmaceuticalingredient, the disease to be treated, the condition of the patient, theage, and gender of the patient, etc. The active pharmaceuticalingredient may be a well-known active pharmaceutical ingredient and aperson having ordinary skill in the art will be able to find informationas to the dosage of each active drug substance and, accordingly, willknow how to determine the amount of each active drug substance in thepharmaceutical composition.

In one aspect described herein, the dose of diclofenac is 12.5 mg. Inanother aspect, the dose of diclofenac is 20 mg. In another aspect, thedose of diclofenac is 25 mg. In another aspect, the dose of diclofenacis 50 mg. In another aspect, the dose of diclofenac is 75 mg. In anotheraspect, the dose of diclofenac is 100 mg. In another aspect, the dose ofdiclofenac is 150 mg. In another aspect, the dose of diclofenac is 200mg. In another aspect, the dose of diclofenac is 250 mg. In anotheraspect, the dose of diclofenac is 300 mg. In another aspect, the dose ofdiclofenac is 350 mg. In another aspect, the dose of diclofenac is 400mg. In another aspect, the dose of diclofenac is 450 mg. In anotheraspect, the dose of diclofenac is 500 mg.

In one embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of mild, moderate, or severe pain stemming fromarthritis.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of mild, moderate, or severe pain stemming fromtendonitis.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of mild, moderate, or severe pain stemming frombursitis.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of mild, moderate, or severe pain stemming fromchronic neuropathies.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of mild, moderate, or severe pain stemming fromshingles.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of mild, moderate, or severe pain stemming fromchronic sports injuries.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of mild, moderate, or severe pain stemming fromchronic malignancies and/or cancer.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of mild, moderate, or severe pain stemming fromchronic radiculopathy.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of mild, moderate, or severe pain stemming fromchronic sciatica.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of pain associated with kidney stones.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of menstrual pain.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of pain associated with endometriosis.

In one embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of inflammation. In another embodiment, the dosagecan contain an amount of diclofenac effective for treatment,amelioration, prophylaxis, or reducing the onset of or symptoms of mild,moderate, or severe fever.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of dysmenorrhea.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of acute migraines.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of osteoarthritis.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of rheumatoid arthritis.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of ankylosing spondylitis.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of spondylarthritis.

In another embodiment, the dosage can contain an amount of diclofenaceffective for treatment, amelioration, prophylaxis, or reducing theonset of or symptoms of gout.

The exact mechanism of action of diclofenac is not entirely known, butwithout being bound to any theory, the primary mechanism thought to beresponsible for diclofenac's anti-inflammatory, antipyretic, andanalgesic action is the inhibition of prostaglandin synthesis byinhibition of cyclooxygenase (COX). In addition, diclofenac appears toexhibit bacteriostatic activity by inhibiting bacterial DNA synthesis.See, Current Medical Research and Opinion (2010) 26 (7): 1715-1731 andInternational Journal of Antimicrobial Agents (2000) 14 (3): 249-251).

In one embodiment, the total dosage of diclofenac administered in a24-hour period is about 20 mg to about 1000 mg per 24-hour periodincluding all iterations of integers within the specified range. Inanother embodiment, the total dosage of diclofenac administered in a24-hour period is about 50 mg to about 250 mg per 24-hour periodincluding all iterations of integers within the specified range. In oneaspect, the total dosage of diclofenac administered in a 24-hour periodis about 50 mg. In another aspect, the total dosage of diclofenacadministered in a 24-hour period is about 100 mg. In another aspect, thetotal dosage of diclofenac administered in a 24-hour period is about 150mg. In another aspect, the total dosage of diclofenac administered in a24-hour period is about 200 mg. In another aspect, the total dosage ofdiclofenac administered in a 24-hour period is about 250 mg. In anotheraspect, the total dosage of diclofenac administered in a 24-hour periodis about 500 mg. In another aspect, the total dosage of diclofenacadministered in a 24-hour period is about 750 mg. In another aspect, thetotal dosage of diclofenac administered in a 24-hour period is about1000 mg.

In another embodiment, the total dosage of diclofenac administered in a24-hour period is about 100 mg to about 150 mg and is effective for thetreatment of osteoarthritis administered in equal daily doses (i.e., 25mg 4 or 5 times daily; 50 mg 2 or 3 times daily; 75 mg 2 times daily;100 or 150 mg 1 time daily; or combinations thereof to reach a desiredtherapeutic efficacy).

In another embodiment, the total dosage of diclofenac administered in a24-hour period is about 150 mg to about 200 mg and is effective for thetreatment of rheumatoid arthritis administered in equal daily doses(i.e., 25 mg 6 or 8 times daily; 50 mg 3 or 4 times daily; 75 mg 2 timesdaily; 100 mg 2 times daily; 150 mg 1 times diallyl; or combinationsthereof to reach a therapeutic efficacy).

In another embodiment, the total dosage of diclofenac administered in a24-hour period is about 100 mg to about 125 mg and is effective for thetreatment of ankylosing spondylitis administered in equal daily doses(i.e., 25 mg 4 or 5 times daily; 50 mg 2 times daily; 100 mg 1 timedaily; or combinations thereof to reach a therapeutic efficacy).

The dosage form can be administered, for example, 1×, 2×, 3×, 4×, 5×,6×, 7×, or 8×, per day. One or more dosage form can be administered, forexample, for 1, 2, 3, 4, 5, 6, 7 days, or even longer. One or moredosage forms can be administered, for example, for 1, 2, 3, 4 weeks, oreven longer. One or more dosage forms can be administered, for example,for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or even longer. One ormore dosage forms can be administered until the patient, subject,mammal, mammal in need thereof, human, or human in need thereof, doesnot require treatment, prophylaxis, or amelioration of any disease orcondition such as, for example, pain.

In another embodiment described herein, the total mass of the matrixfill of the pharmaceutical composition described herein that comprisesan active pharmaceutical ingredient described herein is from about 50 mgto about 500 mg. In one aspect, the total mass of the matrix fill massis about 80 mg. In another aspect, the total mass of the matrix fillmass is about 220 mg. In one aspect, the total mass of the matrix fillmass is about 420 mg. In another aspect, the total mass of the matrixfill mass is about 220 mg. In another aspect, the total mass of thematrix fill mass is about 500 mg.

Described herein are methods for manufacturing matrix fills comprisingan active pharmaceutical ingredient in a controlled release enteric softcapsule in the form of a suspension, where part or all of the activepharmaceutical ingredient is suspended within the matrix fill. Alsoprovided are compositions and formulations where the activepharmaceutical ingredient is incorporated in a one-phase matrix fill. Aone-phase matrix fill can be comprised of a homogeneous mixture of lipidor lipophilic materials.

In one embodiment, a matrix fill as described herein can be manufacturedby adding the specified amounts of wetting agent, lipophilic liquids andsemi-solid lipophilic substance and melting said ingredients at 65° C.under agitation. In a next step, the required amount of hydrophilicpolymer, hydrophilic polysaccharide, and active pharmaceuticalingredient is mixed, homogenized, and de-aired resulting in a matrixfill composition comprising an active pharmaceutical ingredient. In oneaspect, the described matrix fill is encapsulated in a soft capsuleutilizing standard rotary die encapsulation methods. Suitable activeingredients can include, for example, active pharmaceutical ingredients(e.g., therapeutic agents, prophylactic agents, and diagnostic agents),nutraceuticals, vitamins, minerals, and combinations thereof.

Another embodiment described herein is a method for treating,ameliorating the symptoms of, or delaying the onset of a medicalcondition by providing a subject in need thereof with a pharmaceuticalcomposition comprising an enteric soft capsule, as described herein,comprising a pharmaceutical ingredient or ingredients. As used herein, amedical condition can comprise any actual or suspected disease,disorder, or condition that a subject may seek medical care therefor.One embodiment described herein is method of treating, ameliorating thesymptoms of, or delaying the onset of a medical condition of includesadministering a pharmaceutical ingredient having a desired therapeuticor biological activity or suspected of having a desired therapeutic orbiological activity in a subject in need thereof.

In one embodiment described herein, the enteric soft capsule shell andmatrix fills described herein prevent or reduce the onset of esophagealirritation, esophageal erosion, gastric irritation, gastric reflux,peptic ulcers, stomach bleeding, or ulceration from non-steroidalanti-inflammatory drug administration. In one aspect, the enteric softcapsule shell and matrix fills described herein prevent or reduce theonset of esophageal irritation, esophageal erosion, gastric irritation,gastric reflux, peptic ulcers, stomach bleeding, or ulceration fromdiclofenac administration. Without being bound to any theory, it isbelieved that the enteric soft capsule shells are able to prevent,delay, or reduce the onset of esophageal irritation, esophageal erosion,gastric irritation, gastric reflux, peptic ulcers by being easily andquickly swallowed and also by restricting the release of thenon-steroidal anti-inflammatory drug after ingestion to the intestine.Non-steroidal anti-inflammatory drugs can inhibit prostaglandinsynthesis locally in the stomach, which can increase stomach acidity andlead to esophageal damage and stomach ulceration.

In one embodiment described herein, the soft capsules described hereincomprise a matrix fill having controlled, delayed, or extended releaseproperties. Such controlled or extended release matrix fills aredescribed in International Patent Application Publication No. WO2005/009409 and U.S. Patent Application Publication No. US 2006/0115527,both of which are incorporated by reference herein for such teachings.In one aspect, the matrix fill can be configured to provide controlledrelease, extended release, sustained release, delayed release, orcombinations thereof.

Accordingly, one aspect described herein is a controlled release entericsoft capsule having a shell and a matrix fill, wherein the matrix fillincludes an active pharmaceutical ingredient suspended in lipid orlipophilic materials. In another aspect, the lipid or lipophilicmaterial can be a vegetable oil, hydrogenated vegetable oil, fatty acid,wax, fatty acid ester, or a combination thereof.

Accordingly, one embodiment described herein is a controlled releaseenteric soft capsule having a shell and a matrix fill, wherein thematrix fill includes an active pharmaceutical ingredient.

In one embodiment, the active pharmaceutical ingredient can be dispersedor suspended in the liquid carrier. In one embodiment, the activeingredient can be prepared in a self-emulsifying/microemulsifying drugdelivery system (SEDDS/SMEDDS). Optionally, the SEDDS system can includean oil, a surfactant, a cosurfactant or solubilizer, and the activeingredient.

The liquid active ingredients can be prepared to contain the activepharmaceutical ingredient in the range of about 0.005% to about 100%,including all iterations of integers with the specified range, with thebalance made up from non-toxic carrier. Methods for preparation of thesecompositions are known to those skilled in the art. See, for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., 15th Edition, 1975. The liquid portion of the matrix fill cancontain about 0.001% to about 100%, about 0.1% to about 95%, about 1% toabout 90%, about 5% to about 70%, or about 10% to about 50% by weight ofactive ingredient.

In one embodiment descried herein, the enteric soft capsule comprises amatrix fill comprising an active pharmaceutical ingredient comprising atleast one or more fatty acids. In one aspect, the matrix fill comprisesa pharmaceutical composition comprising one or more PUFAs.

In one embodiment, the oral pharmaceutical composition described hereincomprise a matrix fill comprises the composition of Table 8, includingall possible iterations of the specified ranges that provide 100% forthe total weight percentage.

TABLE 8 Exemplary Fatty Acid (FA) Oil Matrix Fills Component PercentWeight (%) Omega-3 FAs 35-99 Omega-6 FAs ≦35 EPA 10-99 DHA  0-75 DPA 1-15 EPA and DHA 40-99 EPA, DHA, and DPA 40-99 Arachidonic acid ≦15Other unsaturated FAs ≦15 Saturated FAs  ≦3 Antioxidants 0.01-5  Fat-soluble Vitamins 0.001-5   

In one embodiment, the pharmaceutical composition comprises acomposition of omega-3 fatty acids comprising at least about 35% to atleast about 95% by weight of all fatty acids in the pharmaceuticalcomposition including all iterations of integers within the specifiedrange. In one aspect, pharmaceutical composition comprises a compositionof omega-3 fatty acids comprising at least about 35% by weight of allfatty acids in pharmaceutical composition. In another aspect, thepharmaceutical composition comprises a composition of omega-3 fattyacids comprising at least about 40% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises a composition of omega-3 fatty acids comprising atleast about 45% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesa composition of omega-3 fatty acids comprising at least about 50% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the omega-3 fatty acids may be a fatty acid, ester,re-esterified triglyceride, or salt thereof.

In another embodiment, the pharmaceutical composition comprises acomposition of omega-3 fatty acids comprising of at least about 50% toat least about 85% by weight of all fatty acids in the pharmaceuticalcomposition. In one aspect, the pharmaceutical composition comprises acomposition of omega-3 fatty acids comprising at least about 50% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises a composition ofomega-3 fatty acids comprising at least about 60% by weight of all fattyacids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises a composition of omega-3 fattyacids comprising at least about 70% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises a composition of omega-3 fatty acids comprising atleast about 80% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the omega-3 fatty acids may be a fattyacid, ester, re-esterified triglyceride, or salt thereof.

In another embodiment, the pharmaceutical composition comprises acomposition of omega-3 fatty acids comprising of at least about 85% toat least about 99% by weight of all fatty acids in the pharmaceuticalcomposition. In one aspect, the pharmaceutical composition comprises acomposition of omega-3 fatty acids comprising at least about 85% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises a composition ofomega-3 fatty acids comprising at least about 90% by weight of all fattyacids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises a composition of omega-3 fattyacids comprising at least about 95% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises a composition of omega-3 fatty acids comprising atleast about 99% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the omega-3 fatty acids may be a fattyacid, ester, re-esterified triglyceride, or salt thereof.

In one embodiment, the pharmaceutical composition comprises omega-6fatty acids in an amount not more than about 20% to not more than about1% by weight of all fatty acids in the pharmaceutical composition. Inone embodiment, the pharmaceutical composition comprises omega-6 fattyacids in an amount not more than about 15% by weight of all fatty acidsin the pharmaceutical composition. In one aspect, the pharmaceuticalcomposition comprises omega-6 fatty acids in an amount not more thanabout 10% by weight of all fatty acids in the pharmaceuticalcomposition. In one aspect, the pharmaceutical composition comprisesomega-6 fatty acids in an amount not more than about 7% by weight of allfatty acids in the pharmaceutical composition. In one aspect, thepharmaceutical composition comprises omega-6 fatty acids in an amountnot more than about 3% by weight of all fatty acids in thepharmaceutical composition. In one aspect, the pharmaceuticalcomposition comprises omega-6 fatty acids in an amount not more thanabout 1% by weight of all fatty acids in the pharmaceutical composition.In one aspect, the pharmaceutical composition comprises essentially noomega-6 fatty acids.

In one embodiment, the pharmaceutical composition comprises EPA. Inanother embodiment, the pharmaceutical composition comprises EPA in anamount of about 10% to about 70% by weight of all fatty acids in thepharmaceutical composition including all iterations of integers withinthe specified range. In another aspect, the pharmaceutical compositioncomprises EPA in an amount of about 20% by weight of all fatty acids inthe pharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA in an amount of about 25% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises EPA in an amount of about 30% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises EPA in an amount ofabout 35% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesEPA in an amount of about 40% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA in an amount of about 45% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises EPA in an amount of about 50% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises EPA in an amount ofabout 55% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesEPA in an amount of about 60% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA in an amount of about 65% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises EPA in an amount of about 70% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the EPA may be a free fatty acid, ester, re-esterifiedtriglyceride, or salt thereof.

In another embodiment, the pharmaceutical composition comprises EPA inan amount of about 70% to about 99% by weight of all fatty acids in thepharmaceutical composition including all iterations of integers withinthe specified range. In one aspect, the pharmaceutical compositioncomprises EPA in an amount of about 75% by weight of all fatty acids inthe pharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA in an amount of about 80% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises EPA in an amount of about 85% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises EPA in an amount ofabout 90% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesEPA in an amount of about 95% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA in an amount of about 99% by weight of allfatty acids in the pharmaceutical composition. In another aspect, theEPA may be a free fatty acid, ester, re-esterified triglyceride, or saltthereof.

In one embodiment, the pharmaceutical composition comprises EPA withsubstantially no DHA (e.g., less than about 5% DHA). In one aspect, theEPA may be a free fatty acid, ester, re-esterified triglyceride, or saltthereof.

In one embodiment, the pharmaceutical composition comprises DHA. Inanother embodiment, the pharmaceutical composition comprises DHA in anamount of about 10% to about 75% by weight of all fatty acids in thepharmaceutical composition including all iterations of integers withinthe specified range. In another embodiment, the pharmaceuticalcomposition comprises DHA in an amount of about 10% to about 50% byweight of all fatty acids in the pharmaceutical composition includingall iterations of integers within the specified range. In one aspect,the pharmaceutical composition comprises DHA in an amount of about 10%by weight of all fatty acids in the pharmaceutical composition. Inanother aspect, the pharmaceutical composition comprises DHA in anamount of about 15% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesDHA in an amount of about 20% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises DHA in an amount of about 25% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises DHA in an amount of about 30% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises DHA in an amount ofabout 35% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesDHA in an amount of about 40% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises DHA in an amount of about 45% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises DHA in an amount of about 55% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises DHA in an amount ofabout 60% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesDHA in an amount of about 65% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises DHA in an amount of about 70% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises DHA in an amount of about 76% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the DHA may be a free fatty acid, ester, re-esterifiedtriglyceride, or salt thereof.

In one embodiment, the pharmaceutical composition comprises DPA. Inanother embodiment, the pharmaceutical composition comprises DPA in anamount of about 1% to about 15% by weight of all fatty acids in thepharmaceutical composition including all iterations of integers withinthe specified range. In one aspect, the pharmaceutical compositioncomprises DPA in an amount of about 1% by weight of all fatty acids inthe pharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises DPA in an amount of about 3% by weight of allfatty acids in the pharmaceutical composition. In another aspect, thepharmaceutical composition comprises DPA in an amount of about 5% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises DPA in an amount ofabout 7% by weight of all fatty acids in the pharmaceutical composition.In another aspect, the pharmaceutical composition comprises DPA in anamount of about 10% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesDPA in an amount of about 13% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the DPA may be a freefatty acid, ester, re-esterified triglyceride, or salt thereof.

In one embodiment, the pharmaceutical composition comprises EPA and DHA.In another embodiment, the pharmaceutical composition comprises EPA andDHA in an amount of about 45% to about 99% by weight of all fatty acidsin the pharmaceutical composition including all iterations of integerswithin the specified range. In another embodiment, the pharmaceuticalcomposition comprises EPA and DHA in an amount of about 60% to about 99%by weight of all fatty acids in the pharmaceutical composition includingall iterations of integers within the specified range. In one aspect,the pharmaceutical composition comprises EPA and DHA in an amount ofabout 60% by weight of all fatty acids in the pharmaceuticalcomposition. In one aspect, the pharmaceutical composition comprises EPAand DHA in an amount of about 75% by weight of all fatty acids in thepharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA and DHA in an amount of about 85% by weight ofall fatty acids in the pharmaceutical composition. In another aspect,the pharmaceutical composition comprises EPA and DHA in an amount ofabout 90% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesEPA and DHA in an amount of about 95% by weight of all fatty acids inthe pharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA and DHA in an amount of about 99% by weight ofall fatty acids in the pharmaceutical composition. In another aspect,the EPA and DHA may be a free fatty acid, ester, re-esterifiedtriglyceride, or salt thereof.

In one embodiment, the pharmaceutical composition comprises EPA, DHA,and DPA. In another embodiment, the pharmaceutical composition comprisesEPA, DHA, and DPA in an amount of about 60% to about 99% by weight ofall fatty acids in the pharmaceutical composition including alliterations of integers within the specified range. In anotherembodiment, the pharmaceutical composition comprises EPA, DHA, and DPAin an amount of about 85% to about 99% by weight of all fatty acids inthe pharmaceutical composition including all iterations of integerswithin the specified range. In one aspect, the pharmaceuticalcomposition comprises EPA, DHA, and DPA in an amount of about 85% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the pharmaceutical composition comprises EPA, DHA, and DPA in anamount of about 90% by weight of all fatty acids in the pharmaceuticalcomposition. In another aspect, the pharmaceutical composition comprisesEPA, DHA, and DPA in an amount of about 95% by weight of all fatty acidsin the pharmaceutical composition. In another aspect, the pharmaceuticalcomposition comprises EPA, DHA, and DPA in an amount of about 99% byweight of all fatty acids in the pharmaceutical composition. In anotheraspect, the EPA, DHA, and DPA may be a free fatty acid, ester,re-esterified triglyceride, or salt thereof.

In one embodiment, the pharmaceutical composition comprises a mixture ofEPA and DHA with one or more fat soluble vitamins. In one aspect, EPAcomprises about 10% to about 70% by weight of the pharmaceuticalcomposition, including each integer within the specified range. Inanother aspect, DHA comprises about 10% to about 70% by weight of thepharmaceutical composition, including each integer within the specifiedrange. In another aspect, at least another fat soluble vitamin comprisesabout 0.005% to about 5% by weight of the pharmaceutical composition,including each integer within the specified range. In another aspect,the pharmaceutical composition comprises about 50% EPA and about 20%DHA, and at least another fat soluble vitamin. In another aspect, thepharmaceutical composition comprises at least about 60% EPA and at leastabout 25% DHA, and at least another fat soluble vitamin. In anotheraspect, the composition comprises at least about 45% EPA and at leastabout 20% DHA, and at least another fat soluble vitamin. In anotheraspect, the composition comprises at least about 46% EPA, at least about18% DHA, and at least another fat soluble vitamin. In another aspect,the composition comprises at least about 30% EPA, at least about 20%DHA, and at least another fat soluble vitamin. In another aspect, amixture of EPA and DHA comprising at least about 45% EPA and at leastabout 18% DHA can be combined in a 99.9:0.1 ratio with cholecalciferol(Vitamin D3) to form a pharmaceutical or nutritional composition; otherfat soluble vitamins described herein and known in the art can be addedat similar weight percentages. In another aspect, the EPA and DHA may bea free fatty acid, ester, re-esterified triglyceride, or salt thereof.

In another embodiment, the pharmaceutical composition comprises lessthan about 30%, less than about 20%, less than about 10%, less thanabout 9%, less than about 8%, less than about 7%, less than about 6%,less than about 5%, less than about 4%, less than about 3%, less thanabout 2%, less than about 1%, less than about 0.5% or less than about0.25%, by weight of the total composition or by weight of the totalfatty acid content, of any unsaturated fatty acid other than EPA, DHA,or DPA. Illustrative examples of any unsaturated fatty acid other thanEPA, DHA, or DPA comprise hexadecatrienoic acid (HTA; all-cis7,10,13-hexadecatrienoic acid), alpha-linolenic acid (ALA;all-cis-9,12,15-octadecatrienoic acid), stearidonic acid (SDA;all-cis-6,9,12,15,-octadecatetraenoic acid), eicosatrienoic acid (ETE;all-cis-11,14,17-eicosatrienoic acid), eicosatetraenoic acid (ETA;all-cis-8,11,14,17-eicosatetraenoic acid), heneicosapentaenoic acid(HPA; all-cis-6,9,12,15,18-heneicosapentaenoic acid),tetracosapentaenoic acid (all-cis-9,12,15,18,21-tetracosapentaenoicacid), tetracosahexaenoic acid (nisinic acid;all-cis-6,9,12,15,18,21-tetracosahexaenoic acid), linoleic acid (LA;all-cis-9,12-octadecadienoic acid), gamma-linolenic acid (GLA;all-cis-6,9,12-octadecatrienoic acid), Calendic acid(8E,10E,12Z-octadecatrienoic acid), Eicosadienoic acid(all-cis-11,14-eicosadienoic acid), dihomo-gamma linolenic acid (DGLA;all-cis-8,11,14-eicosatrienoic acid), arachidonic acid (AA;all-cis-5,8,11,14-eicosatetraenoic acid), docosadienoic acid(all-cis-13,16-docosadienoic acid), Adrenic acid(all-cis-7,10,13,16-docosatetraenoic acid), docosapentaenoic acid(osbond acid; all-cis-4,7,10,13,16-docosapentaenoic acid),tetracosatetraenoic acid (all-cis-9,12,15,18-tetracosatetraenoic acid),tetracosapentaenoic acid (all-cis-6,9,12,15,18-tetracosapentaenoic acid)and free acids, etheyl esters, or other esters or salts thereof.

In one embodiment, the soft enteric capsules comprising fish oil in thematrix fills described herein are stable for months or years. In oneaspect, the pharmaceutical compositions described herein are stable at25° C. and 60% relative humidity (RH) for about 1 month, about 2 months,about 3 months, about 4 months, about 5 months, about 6 months, about 9months, about 10 months, about 11 months, about 12 months, or evenlonger. In another aspect, the pharmaceutical compositions describedherein are stable for 1 year or longer at 25° C. and 60% RH. In anotheraspect, the pharmaceutical compositions described herein are stable for2 years or longer at 25° C. and 60% RH.

In one embodiment, the pharmaceutical composition described herein isprovided as a dosage kit in a dispensing receptacle. In one aspect, thedispensing receptacle is a moisture proof blister pack, strip pack,aluminum blister, transparent or opaque polymer blister with pouch,polypropylene tubes, colored blister materials, tubes, bottles, andbottles optionally containing a child-resistant feature, optionallycomprising a desiccant, such as a molecular sieve or a silica gel. Inanother aspect, the dosage forms are packaged in a dispensingreceptacle, which may optionally be packaged together in a box or otherenclosure. In another aspect, the dispensing receptacle comprisessufficient amounts of the pharmaceutical composition described herein,for 1 day, 2 days, 6 days, 12 days, 24 days, 30 days, 60 days, or 90days of dosing. In another aspect, the unit dosage form is about 250 mgto about 5000 mg of the pharmaceutical composition comprising an entericsoft capsule and matrix fill as described herein. In another aspect, thedosage kit comprises 1, 2, 6, 12, 24, 30, 60, 90, 120, 150, 180, 240,270, or 300 such enteric soft capsules.

In one embodiment, the pharmaceutical composition described hereinprovides a dosage of a fatty acid composition for administration to asubject. In one embodiment, the fatty acid composition can beadministered to a subject without unpleasant side effects, including butnot limited to, gastric disturbances such as eructation (belching),bloating, and unpleasant fishy after tastes (e.g., “fishy burps”). Thedosage form can be administered, for example, to a subject, or a subjectin need thereof. In one aspect, the subject is a mammal, or a mammal inneed thereof. In one aspect, the subject is a human, or human in needthereof. In one aspect, the human or human in need thereof is a medicalpatient. In one aspect, the human subject can be from ˜0 years of age to99 years of age or older including all iterations of integers within thespecified range. In one aspect, the human subject is a child (˜0-9 yearsold) or an adolescent (˜10-17 years old). In one aspect, the subject isfrom 0 to 9 years of age. In another aspect, the human subject is from10 to 17 years of age. In another aspect, the human subject is over 17years of age. In another aspect, the human subject is an adult (≧18years of age).

In another embodiment, a pharmaceutical composition is administered to asubject in an amount sufficient to provide a therapeutically effectivedose of the fatty acids (e.g., fish oil comprising DHA, EPA, or DPA or acombination thereof) described herein of at least about 1 mg to at leastabout 10,000 mg, 25 mg at least about 5000 mg, at least about 50 mg toat least about 3000 mg, at least about 75 mg to at least about 2500 mg,or at least about 100 mg to at least about 1000 mg. In one aspect, thepharmaceutical composition is administered to a subject and comprises atherapeutically effective dosage amount of the fatty acids (e.g., fishoil comprising DHA, EPA, or DPA) of at least about 50 mg, at least about75 mg, at least about 100 mg, at least about 125 mg, at least about 150mg, at least about 175 mg, at least about 200 mg, at least about 225 mg,at least about 250 mg, at least about 275 mg, at least about 300 mg, atleast about 325 mg, at least about 350 mg, at least about 375 mg, atleast about 400 mg, at least about 425 mg, at least about 450 mg, atleast about 475 mg, at least about 500 mg, at least about 525 mg, atleast about 550 mg, at least about 575 mg, at least about 600 mg, atleast about 625 mg, at least about 650 mg, at least about 675 mg, atleast about 700 mg, at least about 725 mg, at least about 750 mg, atleast about 775 mg, at least about 800 mg, at least about 825 mg, atleast about 850 mg, at least about 875 mg, at least about 900 mg, atleast about 925 mg, at least about 950 mg, at least about 975 mg, atleast about 1000 mg, at least about 1025 mg, at least about 1050 mg, atleast about 1075 mg, at least about 1100 mg, at least about 1025 mg, atleast about 1050 mg, at least about 1075 mg, at least about 1200 mg, atleast about 1225 mg, at least about 1250 mg, at least about 1275 mg, atleast about 1300 mg, at least about 1325 mg, at least about 1350 mg, atleast about 1375 mg, at least about 1400 mg, at least about 1425 mg, atleast about 1450 mg, at least about 1475 mg, at least about, 1500 mg, atleast about 1525 mg, at least about 1550 mg, at least about 1575 mg, atleast about 1600 mg, at least about 1625 mg, at least about 1650 mg, atleast about 1675 mg, at least about 1700 mg, at least about 1725 mg, atleast about 1750 mg, at least about 1775 mg, at least about 1800 mg, atleast about 1825 mg, at least about 1850 mg, at least about 1875 mg, atleast about 1900 mg, at least about 1925 mg, at least about 1950 mg, atleast about 1975 mg, at least about 2000 mg, at least about 2025 mg, atleast about 2050 mg, at least about 2075 mg, at least about 2100 mg, atleast about 2125 mg, at least about 2150 mg, at least about 2175 mg, atleast about 2200 mg, at least about 2225 mg, at least about 2250 mg, atleast about 2275 mg, at least about 2300 mg, at least about 2325 mg, atleast about 2350 mg, at least about 2375 mg, at least about 2400 mg, atleast about 2425 mg, at least about 2450 mg, at least about 2475 mg, orat least about 2500 mg, at least about 2550 mg, at least about 2575 mg,at least about 2600 mg, at least about 2625 mg, at least about 2650 mg,at least about 2675 mg, at least about 2700 mg, at least about 2725 mg,at least about 2750 mg, at least about 2775 mg, at least about 2800 mg,at least about 2825 mg, at least about 2850 mg, at least about 2875 mg,at least about 2900 mg, at least about 2925 mg, at least about 3000 mg,at least about 3025 mg, at least about 3050 mg, at least about 3075 mg,at least about 3100 mg, at least about 3125 mg, at least about 3150 mg,at least about 3175 mg, at least about 3200 mg, at least about 3225 mg,at least about 3250 mg, at least about 3275 mg, at least about 3300 mg,at least about 3325 mg, at least about 3350 mg, at least about 3375 mg,at least about 3400 mg, at least about 3425 mg, at least about 3450 mg,at least about 3475 mg, at least about 3500 mg, at least about 3525 mg,at least about 3550 mg, at least about 3600 mg, at least about 3625 mg,at least about 3650 mg, at least about 3675 mg, at least about 3700 mg,at least about 3725 mg, at least about 3750 mg, at least about 3775 mg,at least about 3800 mg, at least about 3825 mg, at least about 3850 mg,at least about 3875 mg, at least about 4000 mg, at least about 4025 mg,at least about 4050 mg, at least about 4075 mg, at least about 4100 mg,4125 mg, at least about 4150 mg, at least about 4175 mg, at least about4200 mg, at least about 4225 mg, at least about 4250 mg, at least about4275 mg, at least about 4300 mg, at least about 4325 mg, at least about4350 mg, at least about 4375 mg, at least about 4400 mg, at least about4425 mg, at least about 4450 mg, at least about 4475 mg, at least about4500 mg, at least about 4525 mg, at least about 4550 mg, at least about4600 mg, at least about 4625 mg, at least about 4650 mg, at least about4675 mg, at least about 4700 mg, at least about 4725 mg, at least about4750 mg, at least about 4775 mg, at least about 4800 mg, at least about4825 mg, at least about 4850 mg, at least about 4875 mg, or at leastabout 5000 mg.

In one embodiment, the effective amount of fatty acids administered to apatient or subject in need thereof of is at least about 250 mg perdosage. In another embodiment, the effective amount of fatty acidsadministered to a patient or subject in need thereof is at least about400 mg per dosage. In another embodiment, the effective amount of fattyacids administered to a patient or subject in need thereof is at leastabout 500 mg per dosage. In another embodiment, the effective amount offatty acids administered to a patient or subject in need thereof is atleast about 600 mg per dosage. In another embodiment, the effectiveamount of fatty acids administered to a patient or subject in needthereof is at least about 800 mg per dosage. In another embodiment, theeffective amount of fatty acids administered to a patient or subject inneed thereof is at least about 900 mg per dosage. In another embodiment,the effective amount of fatty acids administered to a patient or subjectin need thereof is at least about 1000 mg per dosage. In anotherembodiment, the effective amount of fatty acids administered to apatient or subject in need thereof is at least about 1200 mg per dosage.In another embodiment, the effective amount of fatty acids administeredto a patient or subject in need thereof is at least about 1400 mg perdosage. In another embodiment, the effective amount of fatty acidsadministered to a patient or subject in need thereof is at least about2000 mg per dosage. In another embodiment, the effective amount of fattyacids administered to a patient or subject in need thereof is at leastabout 3000 mg per dosage. In another embodiment, the effective amount offatty acids administered to a patient or subject in need thereof is atleast about 4000 mg per dosage.

In one embodiment, the pharmaceutical composition is administered in anamount of at least about 250 mg per day. In one embodiment, thepharmaceutical composition is administered in an amount of at leastabout 500 mg per day. In one embodiment, the pharmaceutical compositionis administered in an amount of at least about 1000 mg per day. Inanother embodiment, the pharmaceutical composition is administered in anamount of at least about 2000 mg per day. In another embodiment, thepharmaceutical composition is administered in an amount of at leastabout 3000 mg per day. In another embodiment, the pharmaceuticalcomposition is administered in an amount of at least about 4000 mg perday. In another embodiment, the pharmaceutical composition isadministered in an amount of at least about 5000 mg per day.

One embodiment described herein is a method for treating, retarding theprogression of, delaying the onset of, prophylaxis of, amelioration of,or reducing the symptoms of a disease related to hyperdyslipidemia usinga pharmaceutical composition as described herein. Another embodimentdescribed herein is a method for treating, retarding the progression of,delaying the onset of, prophylaxis of, amelioration of, or reducing thesymptoms of a cardiovascular-related disease using a pharmaceuticalcomposition as described herein. See U.S. Patent Application PublicationNo. US 2010/0278879, which is incorporated by reference herein for itsspecific teachings of treating cardiovascular-related diseases. The term“cardiovascular-related disease” as used herein refers to any disease ordisorder of the heart or blood vessels (i.e., arteries and veins) or anysymptom thereof. The term “cardiovascular-related disease” as usedherein also refers to any disease or disorder of the heart or bloodvessels (i.e. arteries and veins) or any symptom thereof, or any diseaseor condition that causes or contributes to a cardiovascular disease.”Non-limiting examples of cardiovascular-related diseases include acutecardiac ischemic events, acute myocardial infarction, angina, anginapectoris, arrhythmia, atrial fibrillation, atherosclerosis, arterialfibrillation, cardiac insufficiency, cardiovascular disease, chronicheart failure, chronic stable angina, congestive heart failure, coronaryartery disease, coronary heart disease, deep vein thrombosis, diabetes,diabetes mellitus, diabetic neuropathy, diastolic dysfunction insubjects with diabetes mellitus, edema, essential hypertension, eventualpulmonary embolism, fatty liver disease, heart disease, heart failure,homozygous familial hypercholesterolemia (HoFH), homozygous familialsitosterolemia, hypercholesterolemia, hyperlipidemia, hyperlipidemia inHIV positive subjects, hypertension, hypertriglyceridemia, ischemiccomplications in unstable angina and myocardial infarction, low bloodpressure, metabolic syndrome, mixed dyslipidemia, moderate to mild heartfailure, myocardial infarction, obesity management, paroxysmalatrial/arterial fibrillation/fibrillation/flutter, paroxysmalsupraventricular tachycardias (PSVT), particularly severe or rapid onsetedema, platelet aggregation, primary hypercholesterolemia, primaryhyperlipidemia, pulmonary arterial hypertension, pulmonary hypertension,recurrent hemodynamically unstable ventricular tachycardia (VT),recurrent ventricular arrhythmias, recurrent ventricular fibrillation(VF), ruptured aneurysm, sitosterolemia, stroke, supraventriculartachycardia, symptomatic atrial fibrillation/flutter, tachycardia, typeII diabetes, vascular disease, venous thromboembolism, ventriculararrhythmias, and other cardiovascular events. The term “treatment” asused herein in relation a given disease or disorder, includes, but isnot limited to, inhibiting the disease or disorder, for example,arresting the development of the disease or disorder; relieving thedisease or disorder, for example, causing regression of the disease ordisorder; or relieving a condition caused by or resulting from thedisease or disorder, for example, relieving, preventing or treatingsymptoms of the disease or disorder. The term “prevention” in relationto a given disease or disorder means: preventing the onset of diseasedevelopment if none had occurred, preventing the disease or disorderfrom occurring in a subject that may be predisposed to the disorder ordisease but has not yet been diagnosed as having the disorder ordisease, and/or preventing further disease/disorder development ifalready present.

Another embodiment described herein includes a process of manufacturingenteric soft capsules comprising the pharmaceutical composition asdescribed herein. The process includes preparing a gel mass compositioncomprising a film-forming, water-soluble polymer and an entericacid-insoluble polymer and mixing with appropriate plasticizers andsolvent; casting the gel mass into films or ribbons usingheat-controlled drums or surfaces; and manufacturing an enteric softcapsule comprising a pharmaceutical composition using rotary dietechnology. The thickness of the films or ribbons that form the entericcapsule shell is from about 0.010 inches (≈0.254 mm) to about 0.050inches (≈1.27 mm), including all integers within the specified range.The shell thickness comprises about 0.010 inch (≈0.254 mm), about 0.015inch (≈0.381 mm), about 0.02 in (≈0.508 mm), about 0.03 in (≈0.762 mm),about 0.04 in (≈1.02 mm), or about 0.05 in (≈1.27 mm). In oneembodiment, the thickness is about 0.02 inches (≈0.508 mm) to about0.040 inches (≈1.02 mm). In one embodiment, the shell thickness is about0.028 inches (≈0.711 mm). In another embodiment, the shell thickness isabout 0.033 inches (≈0.838 mm). In another embodiment, the shellthickness is about 0.038 inches (≈0.965 mm).

In one embodiment described herein, the enteric soft capsule shelldescribed herein, encapsulates a pharmaceutical composition as describedherein. In another embodiment described herein, the enteric soft capsuleshell and encapsulated pharmaceutical composition comprises an outerdimension from about 2 oval to about 30 oval including all iterations ofcapsule sizes within the specified range (e.g., 2 oval, 3 oval, 4 oval,5 oval, 6 oval, 7 oval, 8 oval, 10 oval, 12 oval, 16 oval, 20, or 30oval). In another embodiment described herein, the enteric soft capsuleshell and encapsulated pharmaceutical composition comprises a outerdimension from about 2 round to about 28 round including all iterationsof capsule sizes within the specified range (e.g., 2 round, 3 round, 4round, 5 round, 6 round, 7 round, 8 round, 10 round, 12 round, 16 round,20 round or 28 round). In another embodiment described herein, theenteric soft capsule shell and encapsulated pharmaceutical compositioncomprises a outer dimension from about 2 oblong to about 22 oblongincluding all iterations of capsule sizes within the specified range(e.g., 2 oblong, 3 oblong, 4 oblong, 5 oblong, 6 oblong, 7 oblong, 8oblong, 10 oblong, 11, oblong, 12 oblong, 14 oblong, 16 oblong, 20oblong, or 22 oblong). Dimension specifications of soft capsules andtablets are known to those skilled in the art. See Remington'sEssentials of Pharmaceutics, Pharmaceutical Press Publishing Company,London, UK, 1^(st) Edition, 2013, which is incorporated by referenceherein for such teachings.

In another embodiment described herein, the oral pharmaceuticalcomposition described herein is contained and dispensed from a tamperevident packaging. The term “tamper evident” or “tamper resistant”refers to a packaging of any kind that readily displays or allows for anindividual to observe any physical interference or manipulation of saidpackaging. The tamper evident packaging provides reasonable evidence toconsumers that tampering has occurred. The tamper evident packagingadditionally contains appropriate labelling statements describing thefeatures and evidences of the tamper evident packaging. In one aspect,the tamper evident packaging comprises: bottles, film wrappers, blisteror strip packs, bubble packs, heat shrink bands or wrappers, foil,paper, or plastic pouches, container mouth inner seals, tape seals,breakable caps, sealed metal tubes or plastic heat-sealed tubes, sealedcartons, aerosol containers, cans including metal and compositematerials, or any combination thereof. The packaging may also containappropriate instructions for prescribing, instructions for use,warnings, or other appropriate information.

It will be readily apparent to one of ordinary skill in the relevantarts that suitable modifications and adaptations to the compositions,methods, and applications described herein can be made without departingfrom the scope of any embodiments or aspects thereof. The compositionsand methods provided are exemplary and are not intended to limit thescope of any of the specified embodiments. All of the variousembodiments, aspects, and options disclosed herein can be combined inany and all variations or iterations. The scope of the compositions,formulations, methods, and processes described herein include all actualor potential combinations of embodiments, aspects, options, examples,and preferences herein described. The ratios of the mass of anycomponent of any of the formulations disclosed herein to the mass of anyother component in the formulation or to the total mass of the othercomponents in the formulation are hereby disclosed as if they wereexpressly disclosed. All patents and publications cited herein areincorporated by reference herein for the specific teachings thereof.

EXAMPLES Example 1

All-natural enteric soft capsules as described herein were preparedusing the composition shown in Table 9.

TABLE 9 Exemplary Enteric Soft Capsule Formulation Weight Percentage (%)Formu- Formu- Formu- Formu- Formu- Ingredient la 1 la 2 la 3 la 4 la 5Type A Gelatin 0 33.2 0 0 33.2 Type B Gelatin 35.4 0 0 0 0 Fish Gelatin0 0 35.4 0 0 Poultry Gelatin 0 0 0 35.4 0 Glycerol 16 16 16 16 16 Pectin2.6 3.3 2.87 2.87 3.3 Calcium chloride 0.0057 0 0 0 0 Water 45.8 47.545.8 45.8 47.5 Supplemental Water 3 3 3 3 3 TOTAL 103 103 103 103 103

Example 2

All-natural enteric soft capsules as described herein were preparedusing the composition shown in Table 1. The ribbon strength of thegelatin enteric soft capsule composition comprising different Type A andType B gelatins shown in Table 10 was assessed after forming ribbons ofthe gel mass to a thickness of about 0.030 to about 0.045 inches by themethods described herein. The ribbons corresponding to the Type A orType B gelatin enteric soft capsule composition was allowed toequilibrate at room temperature for 60 minutes. The strength of theribbons was measured on a texture analyzer and the ribbon strength wasnormalized to a ribbon thickness of 0.030 inches. The viscosity of theType A or Type B gelatin enteric soft capsule composition gel massdescribed herein was measured on a rotary spindle viscometer. Thenormalized Type A or Type B gelatin enteric soft capsule compositionribbon strength was plotted versus the Type A or Type B gelatin entericsoft capsule composition gel mass viscosity (FIG. 2). The dissolution ofthe gelatin enteric soft capsule compositions described herein werefurther tested for dissolution in phosphate buffer at pH 6.8.

TABLE 10 Exemplary Enteric Soft Capsule Formulation Weight Percentage(%) Ingredient EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 EX 7 EX 8 Type A Gelatin 00 0 0 35.4 35.4 35.4 35.4 Type B Gelatin 35.4 35.4 35.4 35.4 0 0 0 0Glycerol 16 16 16 16 16 16 16 16 Pectin 2.87 2.87 3.28 3.28 2.87 2.873.28 3.28 Water 43 46 43 46 43 46 43 46 Supp. Water 3 3 3 3 3 3 3 3TOTAL 103 103 103 103 103 103 103 103

Example 3 Manufacturing Process for All-Natural Enteric Soft CapsuleShells

The all-natural shell components were dispensed into a heated vesselunder agitation to generate a heated gel mass. Prior to vacuumdeaeration, the heated gel mass was maintained at about 80° C. for atime period of about 0.5 to about 1 hour. Supplemental water was addedto compensate for that evaporated/sublimed during the heating/vacuumdeaeration. Typically, water comprising about 1-5% by weight of the gelmass was lost during deaeration. In order to compensate for this lostsolvent, typically about 3% supplemental water was added to the gel massprior to deaeration. While mixing, heat and vacuum were applied for 1 to5 hours. When cooking completes, the gel mass was transferred intoanother heated vessel and kept at about 60° C. for between 0.5-72 hours.The molten gel mass can be directly transferred to extruders by gravity.

Ribbons were formed via film extrusion. The formed ribbons were fed to arotary die encapsulation machine to form soft capsules. The wedgetemperature was from about 90° C. to about 110° C. The casting drumtemperature was about 45° C. The seam formation takes place viaadhesion. The formed capsules were dried in a tumbling dryer for between15-90 minutes, and then dried on trays in a temperature/humiditycontrolled tunnel for between 12-96 hours.

The process for manufacturing an enteric soft capsule comprising anactive pharmaceutical ingredient as described herein includes preparinga gel mass for the enteric soft capsule described herein; casting thegel mass into films or ribbons using heat-controlled drums or surfaces;and manufacturing an enteric soft capsule described herein comprising amatrix fill using rotary die technology. During this process, the matrixfill is injected in to the lumen as the enteric soft capsule describedherein is formed by rotary die encapsulation.

The finished enteric soft capsules described herein can withstand USPpaddle disintegration tests in acidic media (pH 1.2) for at least 2hours and release active pharmaceutical ingredients in buffered media(pH 6.8).

Example 4

Examples of gel mass compositions useful for producing all-naturalgelatin enteric soft capsules are shown below in Table 11. Compositioncomponents are set forth by weight percentage of the total weight of thegel mass composition.

TABLE 11 Exemplary All Natural Enteric Soft Capsule Gel Mass WeightPercentage (%) Ingredient EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 Type A Gelatin26 30 27 34 37 22 Type B Gelatin 9 5 0 3 0 10 Gelatin Hydrolysate 0 0 10 0 0 Plasticizer 12 8 14 16 15.5 13 Anionic Polymer 3 3 7 3.5 2 3.1Water 50 54 51 43.5 45.5 51.9 Supplemental Water 1 3 2 5 9 7 TOTAL 101103 102 105 109 107 Components and Relational Ratios Total Gelatin 35 3528 37 37 32 Composition Total Enteric and 38 38 35 40.5 39 35.1 GelatinTotal Plasticizer 12 8 14 16 15.5 13 Total Gelatin + 38 38 35 40.5 3935.1 Anionic Polymer Ratio Type A to 2.9 6 — 11.3 — 2.2 Type B GelatinRatio Type A Gel. — — 27 — — — to Gel. Hyd. Ratio of Total Gel. 11.711.7 4.0 10.6 18.5 10.3 to Anion Pol. Ratio of Total Gel. 2.9 4.4 2.02.3 2.4 2.5 to Plasticizer Ratio of Plast. to 4 2.7 2.0 4.6 7.8 4.2Anionic Pol. Weight Percentage (%) Ingredient EX 7 EX 8 EX 9 EX 10 EX 11EX 12 Type A Gelatin 29 31 35 25 28 34 Type B Gelatin 0 0 0 0 0 0Gelatin Hydrolysate 3 2.5 1 0 0 0 Plasticizer 19 16.4 18.7 13.7 19.5 16Anionic Polymer 5 3.2 3.1 3.2 2.9 3.4 Water 44 46.9 42.2 58.1 49.6 46.6Supplemental Water 4 10 8 1 3 4 TOTAL 104 110 108 101 103 104 Componentsand Relational Ratios Total Gelatin 32 33.5 36 25 28 34 CompositionTotal Enteric and 37 36.7 39.1 28.2 30.9 37.4 Gelatin Total Plasticizer19 16.4 18.7 13.7 19.5 16 Total Gelatin + 37 36.7 39.1 28.2 30.9 37.4Anionic Polymer Ratio Type A to — — — — — — Type B Gelatin Ratio Type AGel. 9.7 12.4 35.0 — — — to Gel. Hyd. Ratio of Total Gel. 6.4 10.5 11.67.8 9.7 10 to Anion Pol. Ratio of Total Gel. 1.7 2.0 1.9 1.8 1.4 2.1 toPlasticizer Ratio of Plast. to 3.8 5.1 6.0 4.3 6.7 4.7 Anionic Pol.

Example 5

Examples of all-natural gel mass compositions highlighting the potentialuse of different plasticizers that are useful for producing gelatinenteric soft capsules are shown below in Table 10. Compositioncomponents are set forth by weight percentage of the total weight of thegel mass composition.

TABLE 12 Exemplary All Natural Enteric Soft Capsule Gel Mass WeightPercentage (%) Ingredient EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 Type A Gelatin26 30 27 34 37 22 Type B Gelatin 9 5 0 3 0 10 Gelatin Hydrolysate 0 0 10 0 0 Glycerol 14 16 0 0 0 0 Sorbitol 0 0 14 16 0 0 Triethyl Citrate 0 00 0 14 16 Anionic Polymer 3 3 3.3 3.5 2.45 3.1 Water 48 46 54.7 43.546.55 48.9 Supplemental Water 1 3 2 5 9 7 TOTAL 101 103 102 105 109 107

Example 6

Additional enteric soft capsules as described herein were prepared usingthe composition shown in Table 13.

TABLE 13 Exemplary Enteric Soft Capsule Shell Composition ComponentWeight Percentage (%) Gelatin 29.2 Methacrylic Acid Copolymer 11.15(EUDRAGIT ® L 100) Glycerol 18 Triethyl citrate 1.26 NH₄OH (30%) 1.73Water 38.62

Example 7

Examples of matrix fill formulations useful for gelatin enteric softcapsules are shown below in Table 14. Composition components are setforth by weight percentage of the total weight of the gel masscomposition.

TABLE 14 Exemplary Gelatin Soft Capsule Matrix Fill Formulation WeightPercentage (%) Ingredient EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 Lecithin 0.5 31.5 1.5 1 4 Vegetable oil 22.1 7 12.6 11 35 20 Bees wax 4 4 2.9 2 6 2.9Soybean oil 44.4 50 14.1 35.6 35 30.1 Chitosan 7 9 5 5 2 4 Carbopol ®971 2 7 4 5 1 9 API 20 20 60 40 20 30 Matrix Fill Total 100 100 100 100100 100

Example 8

Additional examples of matrix fill formulations useful for gelatinenteric soft capsules are shown below in Table 15. Compositioncomponents are set forth by weight percentage of the total weight of thegel mass composition.

TABLE 15 Exemplary Gelatin Soft Capsule Matrix Fill Formulation WeightPercentage (%) Ingredient EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 EX 7Polyethylene glycol 84 10 85 35 33 47 22 Glycerol 3 0 6 10 5 0 5Propylene glycol 0 5 0 3 0 10 0 Water 3 5 4 7 5 20 5 API 11 80 5 45 5723 68 Matrix Fill Total 100 100 100 100 100 100 100

Example 9

Examples of matrix fill formulation specifications useful for entericsoft capsules described herein are shown below in Table 16. Compositioncomponents are set forth by weight.

TABLE 16 Exemplary Gelatin Soft Capsule Matrix Fill Formulation Weight(mg) Ingredient EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 EX 7 Diclofenac 25 75 7525 125 150 175 Total Fill Weight 83 270 220 422 220 350 220 RatioDiclofenac to Fill 0.30 0.27 0.34 0.06 0.57 0.43 0.80

Example 10

Enteric soft capsules with a matrix fill comprising diclofenac asdescribed herein were prepared using the composition shown in Table 17and were tested in a two stage delayed release experiment. For theassessment of gastric resistance in the first stage of the experiment,the gelatin enteric soft capsule composition and matrix fill describedherein was placed in 900 mL of 0.1 N HCl pre-equilibrated to 37° C.Samples were taken at 15 min, 30 min, 45 min, and 60 min time points.The samples were syringe filtered and HPLC was run to detect diclofenacrelease. For the assessment of diclofenac delayed release at a pH ofabout 6.8 in the second stage of the experiment, the gelatin entericsoft capsule composition and matrix fill described herein that had beenincubating in 900 mL of 0.1 N HCl pre-equilibrated to 37° C. was removedfrom the 0.1 N HCl and placed in 900 mL of 0.05 M phosphate buffer at pH6.8. Samples were taken at 75 min, 90 min, 105 min, 120 min, 150 min,180 min, 210 min, 360 min, and at 24-hour time points relative to thebeginning of the first stage of the experiment. The samples were syringefiltered and HPLC was run to detect diclofenac release. The percentageof diclofenac release from the gelatin enteric soft capsule compositionand matrix fill described herein was calculated at each time point forthe two tested buffers (FIG. 1).

TABLE 17 Exemplary Gelatin Enteric Soft Capsule Shell with Matrix FillFormulation Ingredient Weight (kg) % Weight Type A Gelatin 4.814 33.2Glycerol 2.3 16 Pectin 0.48 3.3 Water 6.89 47.5 Supplemental Water 0.443 Enteric Soft Capsule Shell TOTAL 14.5 103% Lecithin 0.007 1.45Vegetable oil 0.056 12.56 Bees wax 0.013 2.9 Soybean oil 0.239 53.1Chitosan 0.023 5 Carbopol ® 971 0.023 5 Diclofenac potassium 0.09 20Matrix Fill Total 0.451 100

Example 11

Enteric soft capsules with a matrix fill comprising diclofenac asdescribed herein were prepared using the composition shown in Table 18.The dissolution of the gelatin enteric soft capsule compositions shownin Table 18 were further tested for dissolution in phosphate buffer atpH 6.8 (FIG. 3).

TABLE 18 Exemplary Gelatin Enteric Soft Capsule and Matrix FillFormulations Shell Ingredient Weight Percentage (%) Type A Gelatin 36.07Glycerol 16.26 Pectin 3.34 Water 44.30 Supplemental Water 3 Shell Total103 Weight Percentage (%) Fill Ingredient EX 1 EX 2 EX 3 EX 4 EX 5 EX 6Polyethylene glycol 600 79 67 56 45 33 33 Diclofenac 11 23 34 45 57 57Glycerol 5 0 5 0 5 0 Propylene glycol 0 5 0 5 0 5 Water 5 5 5 5 5 5Matrix Fill Total 100 100 100 100 100 100

Example 12

Enteric soft capsules with a matrix fill comprising diclofenac asdescribed herein were prepared using the composition shown in Table 19and were tested in simulated gastric fluid (SGF) for at least 1 hour andsimulated intestinal fluid (SIF) for at least 1 hour. The entericcapsules were further tested for 2 hours in 0.1 N HCl and for 1 hour inphosphate buffer pH 6.8.

TABLE 19 Exemplary Gelatin Enteric Soft Capsule and Matrix FillFormulations Shell Ingredient Weight Percentage (%) Type A Gelatin 36.07Glycerol 16.26 Pectin 3.34 Water 44.30 Supplemental Water 3 Shell Total103 Fill Ingredient Weight % Weight/cap (mg) Polyethylene glycol 600 63170.1 Diclofenac 27 72.9 Propylene glycol 5 13.5 Water 5 13.5 MatrixFill Total 100 270 Disintegration testing results (n = 12 capsules)Disintegration (1 hr SGF) PASS (n = 12/12) Disintegration (1 hr SIF)PASS (n = 12/12) Disintegration (1 hr phosphate buffer pH 6.8) PASS (n =12/12)

Example 13

Examples of fish oil fill compositions useful in enteric soft capsulesdescribed herein are shown below in Table 20. Composition components areset forth by weight percentage of the total weight of the fillcomposition.

TABLE 20 Exemplary Fish Oil Fill Compositions (1000 mg) WeightPercentage (%) Ingredient EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 EPA 90 94 59 5347 38 DHA ≦10 ≦5 19 20 38 45 DPA ≦5 ≦5 6 5.5 ≦5 ≦5 Arachidonic acid ≦5≦5 2 3 ≦5 ≦5 Other unsaturated FAs ≦5 ≦5 ≦15 ≦15 ≦15 ≦15 Antioxidant 0.50.1 0.25 0.5 0.25 0.25 Total 100 100 100 100 100 100

Example 14

Examples of fish oil fill compositions useful in enteric soft capsulesdescribed herein are shown below in Table 21. Composition components areset forth by weight of the total weight of the fill composition.

TABLE 21 Exemplary Fish Oil Fill Compositions Composition (mg)Ingredient EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 EPA 180 360 540 720 180 360 DHA70 140 210 280 70 140 Fat Soluble Vitamin 0.001 0.001 N/A N/A 0.0010.002 Total 250 500 750 1000 250 500 Composition (mg) Ingredient EX 7 EX8 EX 9 EX 10 EX 11 EX 12 EPA 180 360 162 420 325 650 DHA 70 140 108 250215 250 Total Omega-3 250 500 300 700 600 900 Other Fish Oil 160 320 300300 600 500 Fat Soluble Vitamin 0.001 0.002 0.002 0.002 0.002 0.002Total 410 820 600 1000 1200 1400

What is claimed:
 1. An enteric soft capsule gel mass compositionconsisting of: (a) about 33% to about 36% Type A gelatin by mass; (b)about 3.3% pectin by mass; (c) about 16% glycerol by mass; and theviscosity of the gel mass composition comprises about 20,000 cP to about30,000 cP.
 2. The composition of claim 1, wherein upon extrusion to aribbon, the ribbon comprises a strength of about 1.5 kg to about 2.5 kg.4. The composition of claim 1, wherein the Type A gelatin has a Bloomstrength of about 150 grams to about 350 grams.
 5. The capsule of claim1, wherein the Type A gelatin comprises acid bone gelatin or pig skingelatin.
 6. The composition of claim 1, wherein the Type A gelatincomprises acid bone gelatin.
 7. The composition of claim 1, wherein theType A gelatin comprises pig skin gelatin.
 8. The composition of claim1, wherein the ribbon comprises a thickness of about 0.03 inches toabout 0.045 inches.
 9. A method for preparing the enteric soft capsuleof claim 1, the method comprising: combining the gelatin, pectin,glycerol and water with heating to form a gel mass; and (ii) forming anenteric soft capsule from the gel mass using rotary die technologyfurther comprising a fill comprising one or more active ingredients. 10.The enteric soft capsule formed by the method of claim
 8. 11. Thecapsule of claim 9, wherein the capsule shell does not dissolve insimulated gastric fluid (pH 1.2) for at least 2 hours, and beginsdissolution in simulated intestinal fluid (pH 6.8) within about 10minutes.
 12. The capsule of claim 9, wherein the capsule comprises afill comprising one or more active ingredients.
 13. The capsule of claim9, wherein the capsule comprises a fill of fish oil or non-steroidalanti-inflammatory drug.
 14. An enteric soft capsule comprising a shelland a matrix, the shell consisting of: (a) about 33% to about 36% Type Agelatin by mass; (b) about 3.3% pectin by mass; (c) about 16% glycerolby mass; and the capsule shell comprises a strength of about 1.5 kg toabout 2.5 kg.
 15. The capsule of claim 14, wherein the Type A gelatincomprises acid bone gelatin or pig skin gelatin.
 16. The capsule ofclaim 14, wherein the matrix comprises one or more active ingredients.17. The capsule of claim 14, wherein the capsule shell does not dissolvein simulated gastric fluid (pH 1.2) for at least 2 hours, and beginsdissolution in simulated intestinal fluid (pH 6.8) within about 10minutes.
 18. The capsule of claim 14, wherein the active ingredientcomprises fish oil or on a non-steroidal anti-inflammatory drug.
 19. Thecapsule of claim 18, where in the fish oil comprises eicosapentaenoicacid (EPA), docosahexaenoic acid (DHA), and one or more fat-solublevitamins.
 20. The capsule of claim 18, wherein the non-steroidalanti-inflammatory drug comprises diclofenac.